Alkaloids

MPharm Sem 1
Dr. Punniyakoti
• The term “alkaloid” (alkali-like) is defined as physiologically active basic
compounds of plant origin, in which at least one nitrogen atoms forms part of a
cyclic system.
• The term alkaloid was coined by W. Meissner, a German Pharmacist in 1819.
autonomic
 Functions of Alkaloids
• They may act as reservoirs for protein synthesis.
• They may act as protective substances against the animal or insect attacks due to
bitter taste.
• They may function as plant stimulants or regulators in activities like growth
metabolism and reproduction.
• They may function as detoxifying agents by methylating, condensing, and cyclizing
the compounds whose accumulation might otherwise cause damage to the plant.
Nomenclature
Tests for alkaloids
Physical properties
Isomerization
 Classification

Biosynthetic pathway
In this particular instance, the significance solely lies to the precursor from which the alkaloids are produced in
plant biosynthetically
 Classification: Ring system
1) Phenylethylamine : Ephedrine
2) Pyrrolidine: Hygrine, stachydrine Ephedrine (1) (3,4)
(2)
3) Pyridine or piperidine: Lobeline,
nicotine, piperine, conine,
trigonelline
4) Pyridine-pyrrolidine: Nicotine
5) Tropane: Cocaine, atropine, (5) atropine (5)
hyoschyamine, hyoscine
6) Quinoline: Quinine, quinidine,
cinchonine, cinchonidine
(6)
 Classification: Ring system
7) Isoquinoline: Morphine, codeine,
papaverine, norcotine, tubocurarine,
emetine (9)
(7)
8) Phenanthrene: Morphine, codeine,
thebaine
9) Indole: Reserpine, ergometrine,
strychnine, Yohimbine, serpentine,
physostigmine (11) (12)
10) Tropolone: Colchicine
11) Imidazole: Pilocarpine, pilosine
12) Steroidal: Conessine, solanidine
13) Purine: Caffeine, theobromine
14) Terpene: Aconitine Morphine (8) Colchicine (10)
(13)
Method I
 (v) filter

The resulting crude alkaloid mixture is separated into individual alkaloids by means of fractional
Crystallization, fractional precipitation, column chromatography, partition chromatography,
Gas chromatography or counter current extraction.
 General methods of structure elucidation of alkaloids
• Determination of molecular formula
• Functional group analysis
• Functional nature of O-atoms
• Functional nature of N-atoms
• Estimation of C-methyl moieties, and
• Degradation of alkaloids
1. Determination of molecular formula:
After carrying out the isolation of the alkaloid, it is duly subjected to fractionation by several recognized methods,
namely
 Preparative TLC,
 Preparative HPTLC,
 GC method (for thermolabile alkaloids)
 HPLC methods, and
 Column chromatography
The pure alkaloid, thus obtained is subjected to elemental analysis by using automated CHN analyzer to assign
the empirical formula.
Molecular weight is determined by
MS, Rast method (due to observed depression of the freezing point)
Number of double bond: No. of rings present in an alkaloids can be determine by following formula-CaHbNcOd

Method of complex molecular formulae:

• Methodology pertaining to generalized formula C aHbNcOd
• The number of double bond equivalents may be invariably expressed by
• =a-1/2*b+1/2*c+1
• Atropine formula: C17H23NO3
• According to the equation : 17-1/2*23+1/2*1+1=7
• So atropine consists of 4 double bond equivalents + 3 rings
 H2O

4. Functional group analysis: Presence of various functional groups duly present

in a simple or complex alkaloid by
• FT-IR
• Classical techniques of organic analysis

The next step involves in ascertaining the functional nature oxygen and nitrogen
atoms either in the molecule itself or in its fragments.
• Functional nature of O-atom:
 Alcoholic hydroxyl group
 Phenolic hydroxyl group
 Carboxylic group
 Methoxy group
 Methoxylenedioxyl group, and
 Miscellaneous group (carbonyl, Amide, ester, lactone, lactam groups)
• Functional nature of N-atom
Methylenedioxyl group [-OCH2O-]
 Functional nature of N-atom

Since in majority of the alkaloids the nitrogen atom is involved in a ring structure
(although phenylalkylamine group of alkaloid constitute the exception), it must be a
 e (CaO)
o da lim
/s
 Estimation C-methyl moieties
(Kuhn Rath’s Oxidation method)
• The method for quantifying the number of methyl groups attached to the carbon
atom in an organic molecule, which involves the oxidation of such an organic
compound with chromic acid in the presence of sulfuric acid, followed by steam
distillation to collect the generated acetic acid and quantification of the acetic
acid via acid/base titration.

• In addition, the collected acetic acid can be further analyzed by conversion of

acetic acid into iodoform by hypoiodite.
 Degradation of alkaloids
• In spite of above enormous, valuable, and vital informations with regard to the structure
of an unknown alkaloid, it remains to assign and discover the most preferred structural
system that emphatically and essentially incorporates these substituents moieties.
• Therefore, ultimately the organic chemists are left with no other options than to perform:
 Degradation of unknown alkaloid molecule in a systematic manner, and
 Critical identification of the fragmented entities obtained from degradation step.
Hoffmann’s exhaustive degradation method
Emde’s degradation method
von Braun’s method for tertiary cyclic amines,
Reductive degradation
Alkali fusion
Oxidation,
Dehydrogenation, and Zinc dust/alkali distillation
 Hoffmann’s exhaustive methylation method
• is known as Hoffmann’s exhaustive methylation method.
• It essentially enables two potential clues and information, namely:
• Elimination of N-atom due to cessation of the heterocyclic ring system in an
alkaloid, and
• Residual C-skeleton obtained from above helps in deciphering the actual nature
of the original heterocyclic ring in the alkaloid
Principle:
• Organic compounds having the structural unit , eliminate a
trialkylamine on pyrolysis at 200 oC or above to yield an olefin.
1,4-pentadiene
Limitation of Hoffmann’s exhaustive methylation
 (Y)
(X)
(B)
(A)
Emde’s Emde’s
 c) von Braun’s Method [or Tertiary cyclic amines]
• Makes use of cyanogen bromide (CNBr) which critically brings about the
dealkylation reaction to a tertiary amine.
• is extremely useful in the removal of methyl, allylic, and primary alkyl moieties.
 Hydrolysis/decarboxylation
Emde’s
Hoffmann
Reductive degradation
Zinc-dust distillation

N
Alkali fusion
 Oxidation
• The critical oxidation of an alkaloid provides valuable and informative knowledge
with regard to:
 Basic structure of an alkaloid
 Nature and exact position of the side-chain, and
 Nature and position of the functional moieties (eg., -CHOH; -C=C; -CH 2OH)

o
Vigorous oxidation
Moderate condition
Mild oxidation

• Oxidation of coniine converts the piperidine nucleus to a pyridine

nucleus and also reduces the side chain at C-2 to a carboxyl moiety.
 Dehydrogenation

• During dehydrogenation, peripheral groups such as hydroxyl and C-CH3

are eliminated.
Thus with the help of degradation of alkaloid, exact nature of nucleus, the
various fragments constituting the alkaloid and some types of linkages are
established, thereby enabling the most preferred probable structure of an
unknown alkaloid.
Physical methods