Alkaloids

ALKALOIDS
Prepared by
Bhargav chand Pamula
M. Pharmacy 1st year
Department of
pharmaceutical chemistry
Guided by
Dr. D. Ravi Sankar Reddy
Assistant professor
Acharya nagarjuna university
college of pharmaceutical sciences

Contents :
1. Introducion
2. Classification
3. Isolation
4. Purification
5. Molecular modification and biological activity of alkaloids
6. Structural determination of alkaloids
7. Structural elucidation and stereochemistry of –
■ Ephedrine
■ Morphine
■ Ergot
■ Emetine
■ reserpine

Introduction :
■ Alkaloids are the basic,naturally occurring organic compounds that
contains atleast one nitrogen atom.
■ The term alkaloid was proposed by the pharmacist w.Meissner in 1819.
■ The basic character of alkaloids is due to the presence of lone pair of
electrons on nitrogen.
■ Alkaloids can neutral or acidic when the adjacent functional groups are
electron releasing.
■ These are actually plant secondary metabolites produced as a chemical
defensive mechanism against herbivore, parasites, microorganisms and
viruses.

Classification :
■ Alkaloids are classified into-
1. Phenylethylamine alkaloids-ephedrine, adrenaline
2. Pyrrolidine alkaloids-Hygrine, cuskhygrine
3. Pyridine or piperidine alkaloids-Ricinine, coniine, Piperine
4. Pyridine-pyrrolidine alkaloids-Nicotine
5. Tropane alkaloids-Atropine, Cocaine, procaine, xylocaine
6. Quinoline alkaloids-Quinine, Cinchonine
7. Isoquinoline alkaloids-papaverine, narcotine, Berberine, emetine
8. Phenanthrene alkaloids-Morphine
9. Indole alkaloids-Ergotamine, reserpine,strychnine and brucine
10. Tropolone alkaloids-Colchicine

Alkaloids in food products :
■ Caffeine –present in coffee seeds
■ Theobromine-present in Cacao seeds
■ Theophylline and caffeine – present in tea leaves
■ Tomatine-present in tomatoes
■ Solanine- present in potatoes

Isolation of alkaloids :
■ Before performing isolation we should confirm whether alkaloids are
present or not,for this the plant material is treated with various
alkaloidal reagents such as tannic acid, picric acid, picolinic acid,
perchloric acid, potassium mercuric iodide (Mayer’s reagent ),iodine
dissolved in potassium iodide (Wagner’s reagent ),potassium bismuth
iodide (Dragendorff’s reagent),phosphomolybdic acid (Sonneuschein’s
reagent ),phosphotungstic acid (Scheibler’s reagent) with which
alkaloids give either Precipitate or turbidity.
■ The dried and powdered plant material is first extracted with petroleum
ether if it is rich in fat and then filtered for the removal of soluble fats.

■ The residue is then extracted with methyl alcohol to remove cellulosic
and other insoluble material and the filtrate so obtained is evaporated.
■ The evaporated mass is dissolved in water, acidified to pH 2 and finally
steam distilled to remove methyl alcohol.
■ The dark residual solution is either allowed to stand for several days in
refrigerator or heated with molten paraffin to remove suspended
impurities.
■ The filtrate is extracted with ether or chloroform to remove water
soluble non basic organic material and then steam distilled when steam
volatile alkaloids are separated.
■ The rest of the alkaloid salts is made alkaline and again extracted with
ether or chloroform and the ethereal layer obtained after extraction is
evaporated to give crude alkaloids.

Purification of alkaloids :
■ Purification of alkaloids involves the separation of alkaloids from crude
alkaloid and it can be carried out by –
1. Chramatographic techniques.
2. Gradient pH tetechnique.
Chromatographic techniques:
■ Alkaloidal fractions can be Purified using different chramatographic
techniques.
■ Column chromatography can be Performed by using silica gel or
neutral alumina and chloroform or chloroform with Increased
amounts of methanol are commonly usIng eluents.
■ Detection Is achieved by UV examination.
■ Gas chromatography is used in purification of volatile alkaloids.

■ High performance liquid chromatography (HPLC) is the most effective
technique for Seperation and also for quantitative determination of alkaloids
e.g., solanum, papaver, cinchona, Datura,catharanthus alkaloids .
■ It is useful in Seperation of high molecular weight alkaloids.
Gradient pH technique :
■ Though alkaloids are basic in nature, there are variations in the extent of
basicity of various alkaloids of the same plant.
■ Depending on this character,crude alkaloidal mixture is dissolved in 2 percent
tartaric acid solution and extracted with benzene so that first fraction contain
very weakly basic alkaloids.
■ Then pH of the aqueous solution is increased gradually by 0.5 increments upto
pH 9 and extraction is carried out at each pH level with organic solvent.
■ By this way alkaloids with different basicity are extracted, strong alkaloids
extracted at the end.

Molecular modification and biological activity of alkaloids :
■ Molecular modification is the chemical alteration of the known and
previously characterized Lead compound for enhancing it’s usefulness as
a drug.
■ Several alkaloids are modified molecularly for it’s clinical uses.
Opium alkaloids :
■ Opium ,sun dried latex of the unripe fruit of Papaver Somniferum which
contains atleast 23 alkaloids among them major alkaloids are – morphine,
codeine, thebaine.
■ Morphine has been used as an important agent for the relief of pain.
■ This morphine is modified by methylation with methyl iodide to form
monomethyl morphine also called as codeine.

■ Codeine is used in the relief of mild pain and also used as anti tussive
agent.

■ Another modification of morphine is the esterification of two hydroxyl
groups with acetic anhydride to give heroin.
■ Heroin is more potent than morphine without the respiratory depression
effect.
■ Heroin crosses blood brain barrier more rapidly than morphine and once
it reaches brain heroin hydrolyzes to morphine.

■ Morphine is modified by the addition of methylene groups and the
removal of two hydrogen atoms of hydroxyl groups to give thebaine.
■ It is neither an analgesic nor an anti tussive ,but resembles strychnine
and brucine in its spinal convulsant properties.

Tropane alkaloids :
■ Atropine, scopolamine and cocaine are the tropane alkaloids having
Tropane nucleus .
■ Atropine and scopolamine overlaps in pharmacodynamic activities but
cocaine has uniqueness, being a anesthetic agent.
■ Procaine and lidocaine are local anesthetics derived from cocaine by
molecular modification.

■ Biological activity of some alkaloids are-
■ Tubocurarine - used as muscle relaxant in surgeries .
■ Vincristine, vinblastine – Used as chemotheratic agent in cancers.
■ Ergonovine – used as blood vessel constrictor.
■ Ephedrine – used in bronchial asthma.
■ Quinine – used as anti malarial drug.
■ Quinidine – used in arrythmias.
■ Colchicin – used to treat gout attacks.

General methods of structural determination of alkaloids :
■ Molecular structure of an alkaloid is determined according to the
following steps-
1. First step in determining the structure of a pure alkaloid involves finding
its molecular formula and optical rotatory power.
2. The presence of unsaturation in an alkaloid can be determined by the
addition of bromine or halogen acids or by hydroxylation with dilute
alkaline permanganate.
Reduction may also used to show unsaturation and it can be done by
several reagents like –lithium aluminum hydride and sodium
borohydride.
3. Frequently an alkaloid is cleaved into simple fragments by hydrolysis
with water,acid or alkali and the fragments so obtained are examined
separately so, the structure of fragments can be easily established.

4. Next step involves determining the functional nature of oxygen and
nitrogen atoms either in molecule or in fragments.
5. Functional nature of oxygen : The oxygen atom may be present in the
form of alcoholic or phenolic hydroxyl (-OH), methoxyl (-OCH3 ),acetoxyl (-
OCOCH3), benzoxyl (-OCOC6H5) ,carboxyl (-COOH) or carbonyl (C=O)group.
various oxygen functional groups can be characterized according to the
following charecteristics-
■ Phenolic hydroxyl group (=C-OH) :presence of phenolic hydroxyl group is
characterized by alkali solubility followed by reprecipitation by carbon
dioxide.
■ Alcoholic hydroxyl group (-C-OH) :Presence of alcoholic hydroxyl group is
generally indicated by its acylation reaction along with the negative tests
for phenolic group.

■ Carboxyl group (-COOH) :Presence of the carboxylic group is indicated by its
solubility in weak bases like NaHCO3,NH3, esterification with alcohols.
6. Functional nature of nitrogen : The nitrogen atom may be present as
secondary or tertiary. An alkaloid on distillation with aqueous potassium
hydroxide generally gives methylamine, dimethylamine or trimethylamine
indicates one, two or three alkyl groups attached to the nitrogen.lf ammonia is
formed it indicates free amino group.
7. Estimation of C-methyl groups : C-methyl groups are quantitatively estimated
by heating the compound with acidified potassium dichromate to form acetic
acid which is distilled and estimated against strong base.
8. Degradation of alkaloids : it is the most important step in determining the
structure of a compound Since it give certain products of well known
structures and hence by knowing changes in degradation and structure of
degraded products it will be easy to know structure of original molecule.

9. Physical methods : physical techniques used for determining the
structure of alkaloids are –
– Infrared spectroscopy
– Ultraviolet spectroscopy
– X-ray analysis
– NMR spectroscopy
– Mass spectroscopy
– Optical rotatory dispersion (ORD)

Ephedrine :
■ Ephedrine is an Ephedra alkaloid which has pronounced mydriatic action and
astringent action .It is also used in the treatment of hay fever.
Structural determination :
1. Its molecular formula is C10H15NO.
2. On treatment with nitrous acid, ephedrine gives nitroso compound indicating
the presence of secondary amino group.
3. On benzoylation,it forms dibenzoyl derivative where one benzoyl group
introduced at –NH group and other at –OH group.
4. On oxidation,ephedrine gives benzoic acid that is monosubstituted benzene.
5. Ephedrine when heated with hydrochloric acid forms methylamine and
propiophenone.

Above reaction suggests either of the following two structures to
ephedrine.
6. Ephedrine hydrochloride on heating,undergoes hydramine fission to
form propiophenone, phenylacetone and methylamine.Since the
hydramine fission is characteristic of compounds having C 6H
5CHOH.CH(NHR)CH3 group, ephedrine must be given structure 2.

7. The above structure for ephedrine is supported by its Hofmann
exhaustive methylation to sym-methylphenylethylene oxide.
8. The structure proposed by degradation is further confirmed by its
synthesis and optical isomerism.
■ Racemic ephedrine is synthesised by the catalytic reduction of
benzoylacetyl(1-phenylpropane-1,2-dione) in the presence of
methamine in methanol solution.

■ The Racemic ephedrine is resolved into optically active ephedrine by
mandelic acid.
Optical isomerism in ephedrine :
■ Since ephedrine has two dissimilar asymmetric carbon atoms,four
optically active isomers are possible i.e.two enantiomeric pairs.

Morphine :
■ Morphine is the most important among the opium alkaloids and the
other closely related alkaloids are codeine and thebaine.
■ These three alkaloids are commonly called as morphine alkaloids.
Structural elucidation :
1. Its molecular formula is C17H19NO3.
2. Morphine takes up one mole of methyl iodide to form quaternary
ammonium salt showing that nitrogen is present as tertiary one.
3. Morphine on acetylation or benzoylation gives the diacetyl(heroin) or
dibenzoyl derivative indicating the presence of two hydroxyl groups.
4. By colouration with FeCl3 and solubility in alcoholic aqueous sodium
hydroxide to form monosodium salt which is reconverted into morphine
by passing through CO2. Hence one of the hydroxyl group must be
phenolic one.

5. On treatment with halogen acids,morphine forms monohalogeno
product indicates the presence of alcoholic hydroxyl group.
6. From the unreactivity of the third oxygen atom and the degradation
products of morphine it was concluded that the third oxygen atom is
present as an ether linkage.
7. On catalytic reduction codeine gives isolated dihydro product ,C18H23O3N
suggesting the presence of isolated ethylenic bond.
8. Morphine is brominated to a bromo derivative along with the evolution
of a mole of hydrogen bromide which suggests morphine possesses a
benzene nucleus.
9. Morphine on distillation with zinc dust gives Phenanthrene indicating
the presence of benzene nucleus in morphine molecule.

10. Codeine is treated with methyl iodide to form codeine methiodide,which on
heating with alkali gives α-codeimethine.
■ Based on these changes correspond to Hofmann degradation of N-
methylpiperidine the nitrogen atom must be present in a ring.
11. α-codeimethine on heating with alkali suffers a double bond shift to give
isomeric β-codeimethine. When either of these isomers is treated with methyl
iodide methylmorphenol is formed.This methylmorphenol when heated with
hydrobromic acid gives morphenol which on reduction with sodium and alcohol
gives morphol.

12. Since morphol is obtained by the reduction of morphenol which on
fusion with KOH affords 3,4,5-trihydroxyphenanthrene, the morphenol will
have following structure.
13. Codeine methiodide and codeinone methiodide on heating separately
with a mixture of Ac2O-AcONa gives 3-methoxy-4-acetoxyphenanthrene and
3-methoxy-4,6-diacetoxyphenanthrene.
14. As indicated by the fact that morphine forms monobromo derivative
with bromine and monosodium salt with sodium hydroxide, it possesses
only one benzenoid nucleus .

■ Further,as ethylene is formed as one of the products during the
exhaustive methylation of codeimethines and dimethylaminoethanol is
formed. Thus a –CH2-CH2–Nme chain must be present in morphine.
Further as it contains a double bond and a tertiary nitrogen atom the
partial structure for morphine may be written as below.

15. Codeine on oxidation with chromic acid gives some hydroxycodeine
along with codeine the hydroxycodeine on Hofmann degradation gives a
ketocodeimethine which on heating with Ac2O affords a
methoxydiacetoxyphenanthrene.
16.Struture is further confirmed by X-ray analysis and course synthesis and
is confirmed structure is.

Emetine:
■ Emetine is the principal alkaloid of the roots of cephaelis ipecacuanha.
■ In addition to this ipecacuanha consists cephaeline, psychotrine, o-
methylpsychotrine and emetamine. In common these alkaloids are
known as ipecacuanha alkaloids.
1. Its molecular formula is C29H40N2O4.
2. One of the two nitrogens is found to be present as secondary and the
other as tertiary, but no N-methyl group is present.
3. On heating with hydroiodic acid ,Emetine yields four moles of methyl
Iodide showing the presence of four groups of oxygen.
4. Oxidation of Emetine with permanganate in acetone gives m-hemipinic
acid (1) and small amounts of 6,7-dimethoxyisoquinoline-1-carboxylic
acid (2).

■ Similarly, chromic acid oxidation of Emetine gives 4,5-dimethoxy-
phthalonimide (3). These products indicates the presence of at least one 6,7-
dimethoxyisoquinoline unit in Emetine.
5. Since the absorption spectra of Emetine does not resemble with that of fully
aromatic isoquinoline like papaverine or the acid (2) but is similar to that of
1,2,3,4-tetrahydroisoquinoline derivatives .it must be derivative of
tetrahydroisoquinoline.

6. Ultraviolet absorption spectrum of emetine Closely resembles with that
of tetrahydropapaverine showing that the emetine molecule must
contain two O-dimethoxybenzene units.
7. Emetine on oxidation with alkaline permanganate gives first
corydaldine(4), which removed and the residue is further oxidised to
yield m-hemipinic acid(1).

8. The position of oxide or carboxyl group in compounds (2)(3)(4)
represents the point of attachment of the two tetrahydroisoquinoline units
to the remainder molecule. Since one of the nitrogen atom in Emetine is
tertiary ,the other nitrogen is also linked to rest of the molecule.Hence the
partial structure of emetine may be represented as below.

9. The nature of C4H7 fragment is established by the Hofmann
degradation of emetine so as to remove completely the nitrogen atoms.
10. Going backwards from compound (4) to emetine, full carbon skeleton of
emetine can therefore be depicted as-

■ Now the only problem is to satisfy the third valency of one of the
nitrogens so as to make it tertiary, for this there are three possibilities
to give three different structures for emetine.
11. But R.Robinson proposed the correct structure for emetine as (8),since
emetine has only one C-alkyl group the structure (9),(10)are discarded.
12. Finally the structure was proved by its synthesis.

Ergotamine :
■ Ergotamine is one of the several alkaloids isolated from the ergot or
secale cornutum, product of a filamentous fungus claviceps purpurea
which grows parasitically on rye and other grasses and cereals.
■ It is used in the treatment of migraine headaches.
1. The Molecular formula of ergotamine is C33H35N5O5 .
2. Ergotamine on alkaline hydrolysis gives d-lysergic acid as principal
product and other products which depend upon individual ergot
alkaloid .

■ Hence the complete structure of ergotamine can be studied under two
heads i.e. structure of lysergic acid and structure of non-lysergic acid
moiety.
3. Structure of lysergic acid, C16H19NO2 :
■ By the usual tests lysergic acid is found to contain a carboxylic
group ,non basic amino group of the type >NH,an NCH3 group and a
double bond.
■ On potassium hydroxide fusion,dihydrolysergic acid yields 3,4-
dimethylindole,1-methyl-5-aminonaphthalene and methylamine.

■ This led to the following conclusion.
(a) the presence of indole and naphthalene nuclei in lysergic acid.
(b) the formation of CH3NH2 and 3,4-dimethylindole indicates that the
nitrogen atom of 1-methyl-5-aminonaphthalene is not its own but derived
from the Indole nucleus of the lysergic acid .
■ Lysergic acid on oxidation with HNO3 gives a tricarboxylic acid which on
distillation with soda lime yields quinoline suggesting thereby that
lysergic acid also possesses a quinoline nucleus .It indicates that lysergic
acid must be tetracyclic of the following type.

■ The comparison of uv spectra of lysergic and isolysergic acids with that
of dihydrolysergic acid indicated that the additional double bond of
lysergic acid and isolysergic acids is present in conjunction with the
Indole system i.e.either between C9 and C10 or between C5 and C10.
■ Position of the carboxylic group in lysergic acid is found to be at C8 and it
behaves as β-amino acid.
■ Finally the above structure of lysergic acid is confirmed by its synthesis.
4. Structure of non-lysergic acid moiety :
■ The hydrolysis of ergotamine to Lysergic acid,d-proline, phenylalanine
and pyruvic acid indicates that the alkaloid contain peptide bonds which
on hydrolysis gives amino acids.

■ D-proline and phenylalanine are found to be present as such in the
alkaloid, but the α-keto acid like pyruvic acid is not present as such since
no free keto group is detected in the alkaloid.
■ Since the non-lysergic acid moiety neither contains a free carboxyl group
nor a basic amino group,amino acids are present in the form of a cyclic
structure.
■ Since mild alkaline hydrolysis gives lysergic acid –amide .instead of
lysergic acid ,an acid-amide linkage is present between lysergic acid
carboxyl and the α-hydroxy-α-amino acid moiety.
■ Treatment of dihydroergotamine with hydrazine gives dihydrolysergic
acid hydrazine and propionyl-L-phenyl-alanyl-L-proline.
■ Mild hydrolysis of dihydroergotamine with one equivalent of alkali in
alcohol gives lysergic acid and pyruvoyl-L-phenyl-alanyl-L-proline.

■ The products of above two reactions indicate the following sequence of
the amino acids in the non-lysergic acid moiety.
Pyruvic acid – phenylalanine – proline
■ The products of above two reactions always contain a considerable
quantity of diketopiperazine i.e. phenylalanineproline lactam Suggesting
that in the alkaloid phenylalanine and proline units are linked with each
other in a way to form six membered ring along with five membered ring.
■ Thus the peptide or non-lysergic acid portion of ergotamine may be
written as

■ Thus the complete structure of Ergotamine can be written as below -

Reserpine :
■ Reserpine is the main active principal of the Rauwolfia species.
■ It is used in the treatment of hypertension ,epilepsy.
1. The molecular formula of reserpine is C33H40N2O9 .
2. On heating with HI it gives 5 moles of methyl iodide indicating the
presence of 5 methoxy groups.
3. As reserpine is a weak base, both the nitrogen atoms must be involved
in the ring. Further as reserpine is lack of hydroxyl group,It forms acetyl
derivative indicating the presence of an >NH group. It is further
confirmed by I.R. spectra which reveals the presence of an Indole
nucleus. Reserpine readily gives a methiodide ,so the second nitrogen
atom must be tertiary.

4. Reserpine upon alkaline hydrolysis gives methanol ,3,4,5-trimethoxy-
benzoic acid and reserpic acid of composition C22H28N2O5 .
■ Since reserpine has no –COOH or –OH group the introduction of the two
carboxyl acidic groups (one in 3,4,5-trimethoxybenzoic acid and another
in reserpic acid) and two alcoholic groups (one in CH3OH and the other
in reserpic acid) in the hydrolysis products suggest that reserpine is a
diester.

5. Structure of reserpic acid :
■ By the usual tests reserpic acid is found to possess two methoxy, one
carboxylic, one secondary alcoholic, one >nh, and one tertiary amino
groups.
■ On permanganate oxidation reserpic acid gives 4-methoxy-N-oxalyl
anthranilic acid as one of the products confirming the presence of
indole nucleus.
■ Reserpic acid on fusion with potash gives 5-hydroxyisophthalic acids.
The hydroxyl and carboxyl groups in reserpic acid are meta to each other.
■ Selenium dehydrogenation of methyl reserpate affords a compound of
the C19H16N2 as one of the principal product. This structure is called
yobyrine.

■ Yobyrine condenses with aldehydes suggesting the presence of a
pyridine ring with a >CH2 substituent adjacent to nitrogen. It gives 3-
ethylindole and isoquinoline on zinc dust distillation,phthalic acid on
permanganate oxidation, and o-toluic acid on chronic oxidation.

■ All these reactions suggest the following structure to yobyrine.
■ From the above points we know that one of the methoxy group is in the
m-position to the –NH group of indole. i.e.on C11 .Presence of carboxyl
group at C16 is indicated by the dehydrogenation of reserpic acid with
selenium to 11-hydroxy-16-methylyobyrine.

■ We also know that acidic and hydroxy groups are meta to each other the
hydroxy group in reserpic acid must be present on C18.
■ The second methoxy group is assigned to the position 17.

■ On the basis of reserpic acid structure, reserpine has been assigned the
following structure.
■ The above structure of the reserpine has been proved by its synthesis.

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