Phenanthrene Alkaloids (Due to the presence of phenanthrene in the nucleus)

Morphine (Opium alkaloid):

• Morphine was first alkaloid to be extracted from Papaverum Somniferum and named after
Morpheus, the Greek god of the dreams.
• Isolated by A. Seguin, B. Courtois, in the 1804. But F. W. Sertürner was first to show it a
“vegetal alkali”: the first alkaloid.
• The other two closely related alkaloids are codeine and thebaine. These three alkaloids are
commonly known as Morphine alkaloids and constitute a sub-group of the opium alkaloids.
• Morphine alkaloids show analgesic and sedative properties and can undergo wide variety of
molecular rearrangement.
• It has melting point of 254°C, bitter in taste.
• It is laevorotatory, [α]D = -132.00
• It is insoluble in water and slightly soluble in organic solvents.
• The diacetyl derivative of morphine is used in medicine under the name heroin.
Isolation (Separation Powdered Plant (raw opium)
of opium alkaloids): Extracted in cold with about two to three volume of Methylene Chloride.

Methylene chloride extract Papaverine, Narcotine and gum

a. Evaporated
m b. The residue is extracted with hot dilute Hydrochloric acid, treated with charcoal and then
filtered
Filtrate

Neutralised with ammonia

Papaverine and Narcotine are precipitated out Residue from methylene chloride extract
a. Agitated with water
b. Milled with ten volumes of lime water
Extracted with hot alcohol at temp. below 20°C

(dissolves only papaverine) Lime water extract containing morphine, codeine and thebaine
Residue crude Narcotine
Papaverine precipitated as acid a. Extracted several times with benzene
oxalate to remove codeine and thebaine
b. Neutralised to pH 8.0
Codeine and thebaine Crude morphine ppt.
Purified by recrystallisation Purified a. Filterate is evaporated in vacuum
b. Extracted with amyl alcohol

Crude morphine II (further amount)

 Structure elucidation of Morphine

1. Its molecular formula is C17H19NO3.

2. Nature of nitrogen present: Morphine takes up only one mole of methyl iodide to form
quaternary ammonium salt showing that the nitrogen is present as a tertiary nitrogen.

• Herzig Mayer,s method resulted in release of one mole of methyl amine, indicating that the compound contains
tertiary nitrogen and one of the carbon is methyl.
3. Nature of oxygens present (3 oxygen atoms):

• Morphine on acetylation or benzoylation gives diacetyl (heroin) or dibenzoyl derivative indicating the presence
of two hydroxyl groups.

• Morphine shows formation of monosodium salt with aq. sodium hydroxide which is reconverted to morphine
by passing CO2, it also shows colouration with ferric chloride solution indicating the presence phenolic –OH.
Hence, one of the –OH group must be a phenolic –OH.

• When morphine is treated with halogen acids, it yields monohalogeno derivative, i.e., one hydroxyl group is
replaced by halogen acid. This reaction is characteristic of alcohol. Therefore second hydroxyl group is
alcoholic in nature.
• Morphine on methylation with methyl iodide gives monomethyl product which does not give colour with ferric
chloride, indicating that phenolic hydroxyl is methylated. Codeine is monomethyl ether of morphine.

• The methylated morphine (codeine) on chromic acid oxidation gives a ketone, codeinone, showing that the
monomethylated morphine or codeine has a secondary alcoholic group.

• From the nonreactivity of the third oxygen atom and the degradation product of morphine, it was found that the
third oxygen atom is present as an ether linkage. Removal of ether linkage produces compounds called
Morphinans that has increased activity.
4. On catalytic (palladium) reduction, codeine gives isolated dihydro product, C18H23O3N, suggesting the presence
of an isolated ethylenic bond.

5. Morphine is brominated to a bromo derivative along with the evolution of a mole of hydrogen bromide,
suggesting that morphine possesses a benzene nucleus.

6. Morphine on distillation with zinc dust gives phenanthrene indicating that phenanthrene nucleus is present in
the morphine molecule.
7. Codeine, C18H21NO3 , on treatment with methyl iodide forms codeine methiodide, which on
heating with alkali gives α-codeimethine.

Explained on
next slide

• These changes correspond to the Hofmann degradation of N-methylpiperidine, the nitrogen

atom must be present in a ring.
8. α-codeimethine on heating with alkali suffers a double bond shift to give isomeric β-codeimethine. When these isomers are
treated with methyl iodide followed by alkali, methylmorphenol is formed as the main product alongwith trimethylamine and
ethylene. The methylmorphenol when heated with HBr gives morphenol which on reduction with sodium and alcohol gives
morphol.

1. MeI
2. OH-
Structure of Morphol can be confirmed by its synthesis of its corresponding dimethyl derivative (Pschorr, 1900):

9. Morphol is formed by the reduction of morphenol which on fusion with KOH affords 3,4,5-trihydroxyphenanthrene.

The structure of morphenol and its formation from

codeine establishes the position of two of the three
oxygen atoms of morphine.
10. Codeinone methiodide when heated gives 3-methoxy-4, 6-diacetoxyphenanthrene and
codeine methiodide on heating with a mixture of Ac2O-AcONa gives 3-methoxy-4-acetoxyphenanthrene .

• The presence of an additional acetoxyl group in position

6 in (I) indicates that in (II) the secondary alcoholic group
is lost as water molecule during dehydrogenation to the
aromatic product while in (I) the ketonic group (in place
of secondary alcoholic group) enolises during the route (II)
to aromatic product and hence it appears as acetoxy
group in the final product.
• Thus the position of all the three oxygen atoms in
morphine has been established, one phenolic at C-3, the
other present in ether linkage between C-4 and C-5 and
third in secondary alcoholic group at C-6 of
phenanthrene nucleus.
(I)
11. From the observed facts such as:
• morphine forms monobromo derivative with bromine.
• Morphine forms monosodium salt with sodium hydroxide.

• Ethylene is formed as one of the product during the exhaustive methylation of codeimethines in point 8.
• Dimethylaminoethanol is formed in point 10.

• Further it contains a isolated double bond and a tertiary nitrogen atom which is cyclic in nature.

• The partial structure of morphine may be written as below.

• Now the problem is to assign the

positions of double bond and the chain –
CH2-CH2-NMe in such a manner so as to
explain all the reactions of morphine
12. Point of attachment of
• Codeine (methylated morphine) when oxidized gently with chromic acid yields some
hydroxyl codeine along with codeinone. The hydroxy codeine when subjected to exhaustive
methylation yields ketocodeimethine which on heating with Ac2O yields methoxy diacetoxy
phenanthrene. The latter when oxidized further yields a quinine with loss of acetoxy group.
Thus, all these reaction may be summarized as follows:
• The loss of acetyl group during the last oxidation
indicates that one of the two acetoxyl groups in
methoxydiacetoxyphenanthrene must be present at C9
or at C10.

• Now since this acetoxyl group, which is lost in the

oxidation is inserted in this position via the ketonic
group during the acetolysis, it means that the keto
group in keto codemethine and therefore the new
hydroxyl group in hydroxy codeine should be present at
C9 or C10.

• The new secondary alcoholic group of hydroxycodeine

is converted into ketonic group during Hofmann
degradation and double bond must be introduced
between C-9 and C-10 during fission of nitrogen ring
and thus the nitrogen must be linked at position C-9 or
C-10. The exact point of linkage i.e., C-9 is established
only after synthesis of morphine.
• It is observed that the side chain
having nitrogen is always eliminated
with the aromatization of nucleus.

• Gulland and Robinson stated that the

formation of the phenanthrene
derivative can take place for structural
reasons unless the ethamine chain is
displaced.

• Since nitrogen is placed at C-9, the

carbon end of the side chain must be
attached at an angular position (C-13
or C-14), so that its extrusion from the
position resulted in aromatization.
• The C-13 is selected on the basis that such structure
explains the rearrangement of thebaine to thebenine.
• Schopf’s experiments involving the Beckmann
rearrangement of the oxime derived from
dihydrocodeinone. These experiments yielded aldehyde
nitrile and not keto nitrile. Confirming attachment C-
terminus of ethylamine chain at C-13 carbon.
• The partial structure for morphine can now be written
as:

10
13
14

• Now the only problem is to assign the position of the

double bond.
https://image.slidesharecdn.com/morphine-structuralelucidation-2-140306024725-phpapp01/95/morphine-
structural-elucidation2-8-638.jpg?cb=1394074156
13. Position of the double bond:
• Codeine when treated with PCl5, yields α-chlorocodide which on treatment with aqueous acetic acid gives the
mixture of codeine, isocodeine, pseudocodeine and allopseudocodeine (positional isomers).
• First two give same ketone on oxidation indicating that they differ only in the position of the hydroxyl group
which is at C-6;
• while, the latter two give same ketone on oxidation again suggesting that these two differ in the position of –OH
group which is at C-8.
• These changes can be explained if the double bond is in between C-7 and C-8.
• The morpine and codeine can be drawn as below:

Aq.AcOH

pseudocodeine
α-chlorocodide

isocodeine allopseudocodeine
14. The above proposed structure has been confirmed by X-ray analysis and the coursed synthesis.
(i) Gates et al., (1956):
nitrosylation

2,6 dihydroxynaphthalene

1,2 naphthaquinone derivative

Nitrosylation
Saponification

reduction
oxidation
(Mcconnellite)

NH2NH2
/KOH
Secondary
alcohols changes
to ketone

Gates intermediate
Codeine
PYRIDINE or PIPERIDINE ALKALOIDS

CONIINE (Hemlock alkaloid):

• It is the principal alkaloid of poison hemlock (Conium maculatum).
• Its crude extract was used as poison by ancient GREEK for the execution of criminals. The
famous Greek philosopher SOCRATES was executed to death by drinking poison Hemlock.
• CONIINE is the major constituent of Hemlock alkaloids out of five alkaloids belonging to
Hemlock. These are
CONIINE, γ-coniceine, conhydrine, pseudoconhydrine, and N-methylconiine.
• Poisonous property of hemlock is due to coniine.
• It paralyses the CNS and the motor nerves which control the muscles causing death by
cessation of breathing.
• Coniine was the first natural compound to be synthesized (1886).
• It is a colourless liquid (b pt. 167°C), readily soluble in organic solvents, has unpleasant odour
and burning taste. Coniine is optically active [α]D +15.7O
Constitution of Coniine:
1. Its molecular formula is C8H17N on the basis of molecular weight determination and
elemental analysis.
2. On zinc dust distillation, coniine loses six hydrogen atom to give conyrine, C8H11N, which on
oxidation with KMnO4 yields pyridine-2-carboxylic acid (α-picolinic acid).
The formation of α-picolinic acid indicates that conyrine is 2-substituted pyridine and coniine
is 2-substituted piperidine.

3. Since the difference in molecular formulae of conyrine (C8H11N) and pyridine (C5H5N) is C3H6,
the side chain in position 2 may be –propyl (-CH2CH2CH3) or isopropyl (CHMe2).
On the basis of above discussion, Coniine can have one out of two structures I or II.
4. Structure of coniine was found to be I on the basis of some observations as:

• Coniine on heating with HI at 300°C under pressure gives n-octane and no iso-octane which was the expected product in case
of structure II.
• Complete exhaustive methylation of coniine followed by reduction gives n-octane.
• Von Braun degradation gives 1,5-dichloro-octane which is characteristics of secondary amine.
These observation can be explained on the basis of Structure I as:
5. Finally the structure proposed by degradation is confirmed by its synthesis.

i). Ladenberg’s synthesis

ii). Diel’s-Alder synthesis:

1. Hydrolysis
2. -3CO2

1. Hydrolysis
2. -CO2
8H 2H
Van Braun
degradation
(± Coniine)
iii). Bergmann method:

• 2-methylpyridine is converted to the corresponding alkyl lithium compound using phenyl lithium.
• Nucleophilic substitution using bromo ethane. Which is then followed by
• reduction using sodium in ethanol as in the Ladenburg synthesis