1. Morphine and atropine

2. Morphine

3. Introduction:- It is important among the opium alkaloid.
The amout being nearly 3-23%
The other two closely related alkaloids are codeine and thebaine
Due to the presence of phenanthrene nucleus these are also known as phenanthere
alkaloids

4. Source:- opium or gum opium poppy or poppy capsules
It is obtainted from dried latex of unripe capsules of papavarine species(by
Vertical incisions 0.1 to 0.5 mm depth)
Papavarine sominiferum
P . bractatum
P . oriantale
P . rhoeaes
Commercial varieties :-
Turkis opium
Indian opium
Chainese opium
Russian opium

5. Isolation:-

6. Extracted several times with benzene to remove codeine
And thebaine

8. Properties and uses:- Morphine is colorless prismatic substance
2. M.Pt :254oc
3. Bitter in taste
4. Levo rotatory
Insoluble in water, little soluble in benzol, ether , chloroform sufficiently soluble in
alcohol and alkali solution
Used as analgesic and sedative
Depressant action on various parts of the nervous system but habit forming.
Diacetyl derivative of mophine- heroin (more habit forming than morphine)
10. Codeine sulfate less effective anagesic and antitussive causes addiction
11.Thebaine little medicinal values and produces convulsions

9. Constitution Molecular formula Nature of nitrogen Nature of oxygen
Presence of ethylenic bond
Presence of benzene neucleus
Presence of cyclic tertiary base system
Presence of phenanthrene moiety
1)structure of methyl morphol
2)presence of N-Methyl group
3)position of 3 oxygen atoms
4)structure of morphenol
5)structure of mophine
6)point of linkage of –CH2-CH2-N-CH3 chain
7)position of double bond
Synthesis

10. Molecular formula:-
C17H19O3N
Nature of nitrogen:-
nitrogen is tertiary in nature
Nature of oxygen atom:-
i) Presence of 2 hydroxyl groups

11. ii) Nature of hydroxyl groups:-
With FeCl3 gives characteristic color
treating with aq.NaOH gives soluble mono sodium salt of morphine
reconverted into morphine with CO2
Note:- one of the two hydroxyl groups is phenolic in nature
iii) With halogen acid gives monohalogen derivative that is one –OH group is replaced
by halogen acid this reaction is characteristic of alcohol. Hence second –OH group
is alcoholic in nature (secondary alcohol)
iv) From the unreactivity of third oxygen and by degradation studies it is revealed that
third oxygen is in ether linkage
Presence of ethylenic bond:-
when codeine is reduced catalytically in the presence of Pd it takes one molecule
of hydrogen.
Presence of benzene nucleus:-
a) bromination :-gives mono bromo derivatives it reveals that morphine contain
benzene ring.

12. Presence of cyclic tertiary base system:-
Presence of phenanthrene ring:-
with zinc dust :- gives phenanthrene moiety –contain phenanthrene moiety
Presence of cyclic tertiary base system:-
this is confirmed by the fat that codeine when subjected to exhaustive methylation,
yield codeine , the formula of which contains one more CH2 than codeine itself
and the nitrogen atom remains intact i.e., it is not lost.
If codeine possess a cyclic t-amino system, then the product obtained would posses
lesser number of carbon atoms and there also occurs loss of nitrogen
If codeine contains a tertiary cyclic base system, the result are than readily explained
by the following reactions:-

13. Structure of methyl morphol:- by pschorr synthesis;-
Heating with
alkali
-codeimethine
-codeimethine
Morphol
Methyl morphenol
morphenol
HBr
Na\C2H5OH
Na\C2H5OH
HBr
Methyl morphol
Presence of CH2CH2NCH3 group:-
codiemethiodide and codinenemethiodide on heating separately with a mixture
of AC2O-ACONa gives 3-methoxy 4-acetoxy phenanthere and 3-methoxy-
4,6-diacetoxy phenanthrene along with dimethyl amino ethanol respectively.
which reveals the presence of CH2CH2NCH3 group

15. Methyl morphol
further confirmed by:-

16. Presence N-Methyl groups:-.
By herzig-mayer method one >N-CH3 group is present
Presence of third oxygen atom and ether linkage:-
The above reaction explains the placing two oxygen atoms in the form of –OH
present at c-3 and C-6. And the second oxygen is ether linkage between C-4 and
C-5 of phenanthrene nucleus

17. Structure of morphine:-by the above information we can know that the presence of
following groups
Position of double bond:-codeine on treating with PCl5 gives chlorocodide further
Hydrolysis with acetic acid gives mixture of codeine, isocodeine, psuedocodeine,
and allopsuedocodeine. In which psuedocodeine on oxidation gives pseudocodinone
( -C=O group at C-8 Position). By above results the double bond is present as:-

18. Formation of 9-amino phenanthrene indicates the N-CH3 group of morphine is
attached to C-9. Further position of N-CH3group at 9th position is supported by
Steric view.

19. After several chemical reactions the tertiary nitrogen attached through ethylene
Bridge and attached to C-13.And hence the mophine structure can be given as:-

20. Further confirmed by synthesis:-GATES synthesis

23. SAR of morphine :- A-aromatic ring B-cyclo hexane C-cyclo hexane
D-pyridine
E-tetra hydrofuran
At 3,6 position,-OH groups:-
Conversion of 3-OH to 3-methoxy gives
codeine-decreases activity upto 15% of
morphine
Conversion of 6-OH to 6-methoxy gives
heterocodeine- increases 6fold activity
Of morphine
Oxidation of 6-OH gives ketone –decreases
the activity
Note:-absence of 7,8 double bond in morphine --- decreases the activity 37%\
Absence of double bond and presence of ketone ----increases the activity

24. Removal of 6-OH (desoxymorphine) increases 10 fold in the dihydro series
Acetylation of morphine:-
heroin—2-3 times more potent than morphine
If the ether linkage is opened up, to offered secondary alcohol on the aromatic ring
at the 4th position—decreases activity drasticaliy
Uses :-
Analgesic
Hypnotic and sedative
Potent analgesic due to its central narcotic effect
CTZ stimulation in the medulla
Codeine is used as antitussive
Heroin is used as more narcotic and analgesic (habit forming drug)
Apomorphine has emetic action
Dihydromorphine –potent narcotic drug
Synthetic morphine compounds lilke opiods which are non habit forming but possess
the medicinal activity of mophine

25. Atropine

26. Introduction:- Prominent tropane alkaloid is atropine
Source:-deadly night shade atropa belladona , a thorn plant datura stromanium,
in plants available as L-hyoscyamine
hyoscyamine on heating gives + hyoscyamin
recemic mixture of hyoscyamin is known as atropine
Physical properties:-
Color:- colorless
State :-crystals
Odour:-odourless
Taste :-bitter
Solubility:-sparingly soluble in water
and soluble in organic solvents
Melting point:-118oc

27. Isolation:- Constitution:-
Atropine is extracted either from belladona roots or from the juice of datura plant
In practice the juice which also contains hyoscyamine is heated with K2CO3 solution
When hyoscyamine is recimised to atropine then this atropine is extracted with
chloroform.
The chloroform is recovered by evoparation and the residue is then extracted with
dil. H2SO4 This solution made alkaline with K2CO3 when atropine
is ppted out.
The ppted atropine is extracted with ether and purified by converting into an oxalate
or sulphate
Constitution:-
Molecular formula:- C17H23NO3
Atropine structure is established by hydrolytic degradation process

28. Determination of structure of tropic acid :-
Atropine on hydrolysis gave tropine so it is an ester of tropic acid hence atropine
Is considered as tropine tropate
Determination of structure of tropic acid :-
Mol.Formula:-C9H10O3
Tropic acid with bromine gives no decolorisation of bromine indicate
saturated compound (absence of double bond).
2. Formation of monosodium salt of tropic acid indicates that tropic acid
consists of a single carboxylic acid.
Absence of phenolic OH group is observed by FeCl3
From 1 and 2 it can be predicted that tropic acid is saturated mono carboxylic acid

29. By the above oxidation process it is observed that atropic acid and in turn tropic
acid consists of benzene molecule with a substituent
Hence the structure can be written as :-

30. On acetylation mono acetyl derivative is obtained it indicates that presence of hydroxyl
group.
The 2 possible structures that can be drawn for the molecular formula of atropic acid
are
Further structure of atropic acid is confirmed by oxidising tropic acid in KMnO4
Phenyl glyoxal is the same oxidation product of atopic acid

31. As the tropic acid consists of primary alcohol functional group the probable structure
of tropic acid will be

32. Further structure of the tropic acid is established by its synthesis
(Mekenje and Wood )

33. The tropic acid formed is recemic mixture.
Determination of structure of tropine:-
mol.formula:-C8H15NO
Tropine reacts with bromine no decolorisation is seen hence it is a saturated comp.
Tropine when reacts with methyl iodide it consumes 1 mole to give a quaternary
ammonium salt
It indicates that nitrogen atom in tropine is tertiary in nature
Detection of presence of N-Methyl group:- herzig meyer method

34. The amount of AgI formed is equal to 1 methy group indicating that the nitrogen
in tropine is substituted with methyl group
Nature of oxygen atom:-
Indicates presence of OH group
Detection of basic nucleus:-
Tropine on oxidation gives ketone it indicates presence of secondary alcohol
tropinone on oxidation gives tropinic acid which on further oxidation gives
N-methyl succinamide it reveals that presence of N-methyl pyrollidine ring in
tropinone and hence in tropine.

35. The presence of N-methyl pyrollidine ring accounts for 5 carbon atoms as against the
8 carbon atoms present in tropine. As the latter compound is a dibasic acid it means that
The remaining 3 carbon atoms must be present as COOH and CH2COOH groups. The
two groups attached to various and positions in that pyrollidine ring .
The positions have been ascertained as follows:-

36. Tropic acid on hoffmann exhaustive methylation yields a unsaturated dicarboxylic
acid which on reduction gives pimelic acid
As pimelic acid has 7 carbon atoms joined in series it means that tropinic acid
also contain 7 carbon atoms in similar fashion
but the difference that its 8th carbon atom is present in N-CH3 this is only possible if the
two groups COOH and CH2COOH are attached to and positions this reaction
reveals that the tropinone similar to Tropinic acid has also 7 membered carbon ring this
confirmed by the dehydration of Tropine yields tropidine which on H.E.M yields
cycloheptatriene or tropilidene the reduction of latter compound yields cycloheptane

37. There is another important reaction which reveals structure of tropine

38. Formation of 2-ethyl pyridine reveals the presence of a reduced pyridine ring in the
tropine molecule
By the above discussion conclusions are:
Tropine possess a 7 membered carbon ring.
It contains a reduced pyridine ring in the structure
It possess reduced pyrrole (pyrollidine) ring in the structure
It possess N-Methyl group
As tropine contains only one nitrogen atom it means that this should also remain
common to pyrollidine and piperidine( reduced pyridine ) rings and it should be as
N- CH3 group

39. Atropine structure:- Tropine may also written as:-
Tropine Tropic acid +

40. Fischer esterification:-
Atropine structure confirmed by Synthesis:-
Fischer esterification:-
ATROPINE

41. USES:- Anticholinergic agent. Smooth muscle relaxant – antispasmodic.
Pupil dialation. A single drop of solution containing one part of atropine in 40,000
parts of water is sufficient to dialate the pupil of the eye
Atropine has also been used to relive the night sweats which are a distressing
feature of tuberculosis and to deminish the activity of salivary and gastric glands

42. References:- Chemistry of natural products – o.p agarwal
Chemistry of natural products by chetwal

43. thanq