5 memberd heterocyclic compound pyrrol

1. A Seminar On
“Organic Chemistry of Five Membered
Hetrocyclic Compound : Pyrrole”
Submitted To
SAVITRIBAI PHULE PUNE UNIVERSITY, PUNE
By
Ms. Bhalekar Pournima Ashok
M Pharm Sem I
(Department Of Pharmaceutical Chemistry
Roll no :CH101)
Under the guidance of
Dr. S. B. Jadhav
( HOD, Pharmacutical chemistry)
Progressive Education Society’s
Modern College Of Pharmacy, Nigdi, Pune-44.
(2016-17)
1

2. Contents
• Introduction: heterocyclic compounds
• Introduction: pyrrole
• Nomenclature
• Physical properties
• Chemical properties/ reaction
• Derivatives of pyrrole
• Synthesis of pyrrole
•Application
• References 2

3. 3
Introduction:
Heterocyclic Compounds
1.

4. 4
 A cyclic organic compound containing all carbon atoms in
ring formation is referred to as a carbocyclic compound.
Heterocyclic compounds are organic compounds that
contain a ring structure containing atoms in addition to
carbon, such as sulfur, oxygen or nitrogen, as the
heteroatom. The ring may be aromatic or non-aromatica.
Number of drugs in pharmaceutical science are heterocyclic
compounds.
 Heterocyclic compounds may be of natural origin or
synthetically available.

5. 5
Classification of Heterocyclic compounds
5- Membered
heterocyclic
compounds
One heterotom:
Example-furone
pyrrole
More than one
heteroatom:
Example- Pyrazole
Imidazole
Oxazole
6-Membered heterocyclic
compounds
One heteroatom
Example- Pyridine,
piperidine
More than one
heteroatom:
Example- pyrimidine
7-Membered
heterocyclic
compounds
Example:
Oxepine
Condensed
heterocyclic
compounds
Example: Indole,
Quinoline
Isoquinoline

6. 6
 5- Membered heterocyclic compound having one
heteroatom:
 5- Membered heterocyclic compound having more than one
heteroatom
furan Pyrrole Thiophene
Pyrazole Oxazole Imidazole

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 6-Membered heterocyclic compounds having one heteroatom:
Pyridine Piperidine
 6-Membered heterocyclic compounds having more than one heteroatom:
Pyrimidine Pyrazine

8. 8
 7-Membered heterocyclic compounds
1-H-Azpine Oxepine
 Condensed heterocyclic compounds
Quinoline
Isoquinoline

9. 9
Introduction: Pyrrole
2.

10. 10
 HISTORY
1834 Runge
Distillation of coal tar, bone oil, and
other product derived from proteins
gave unknown product in ammonia &
dipped in HCl, called PYRROLE
1857 Anderson
Obtained pure compound from bone
oil distillate and synthesized by the
pyrolysis of ammonium mucate which
is commercially used.

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 Pyrrole is the 5- membered ring containing N-atom replacement with C-
atom.
 the pyrrole ring system soon become of great interest, as it was found in
many compounds widely distributed in nature.
 Pyrrole rings are present in a number of natural products for eg. alkoloids
and synthetic pharmaceuticals.
 Pyrroles having a following therapeutical activity

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Nomenclature
3.

13. 13
 In naming pyrrole and its derivatives, the nitrogen atom is
assigned position-1.
1
2
3
4
5 α‘
β’ β
α
 The position of the substituent may be specified in
Arabic numerals or in Greek letters.

14. 14
 Three dihydropyrroles or pyrrolines are theoretically possible
and tetrahydropyrrole is called pyrrolidine. The pyrrole ring, when
considered as asubstituent in another structure is called pyrryl.
Pyrroline
 Five - membered heterocycles containing nitrogen general end
with ‘ ole’
Pyrrolidine Pyrryl

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Physical properties
4.

16. 16
 It is a colourless volatile liquid.
 It’s boiling point is 131°C and melting point is -23°C.
 It turns brown in the air and gradually resinifies.
 Only slightly soluble in water but it is totally miscible with
ether and ethanol.
 Pyrrole is weakly basic in nature.
 Pyrrole has a relatively high boiling point as compared to
furan and thiophene, this is due to the presence of
intermolecular hydrogen bonding in pyrrole.

17. 17
Aromaticity of pyrrole
 Pyrrole itself is completely planar and have molecular dimensions.
 The 5 Sp2 hybridised C-atom sustained 6π electron system. From
the molecular orbital standpoint is consisting of planar pentagoan
with Sp2 hybridised C-atoms.
 Each of the 4 C-atoms has one electron remaning in a pz orbital.
The N-atom has 2 electron in p orbital.
 These p orbitals overlap to give a total of six electrons in π
system and this shell provide stability.
 Pyrrole is an extremely weak base because its pair of non-bonding
electrons are part of the π-cloud (Kb = 2.5 x 10-14). Therefore, if
pyrrole is protonated, it loses its aromaticity.

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 They tend to react by electrophilic substitution due appearance of
–ve charge on carbon atoms.
 Due to delocalization of electron as shown in the following
resonance structures .

19. 19
Chemical properties/ Reaction
5.

20. 20
 Pyrrole is aromatic and more reactive than benzene.
 It gives electrophilic substitution reactions such as halogenation ,
nitration ,etc.
 It also undergoes diazotization and Reimer-Tiemann reactions,
while benzene does not.
 Acidity
pKa = 17,5
 Pyrrole is a weak acid
 Pyrrolyl anion is a strong base

21. 21
 Basicity
Pyrrole is a weak base: Protonation breaks aromaticity (lone pair
participates in conjugation)and thus it is not readily available

22. 22
1. Opening of the pyrrole ring:
 The pyrrole ring is not readily opened by acids or alkalis, but
boiling with alcoholic hydroxylamine hydrochloride causes
rupture, with the formation of succindialdehyde dioxime.
N
H
H
N
H
H2
NH2OH
-H
N
H
H2
NHOH
H
N
H NOH
H
-H
HN
NOH
NH2OH
-NH3
HON NOH
succindialdehyde dioxime

23. 23
 The ozonolysis of pyrrole and derivatives at -60 OC in
chloroform breaks the ring.
 Pyrrole in aq. Silver nitrate is broken down byy ultrasonic
vibration into acetylene and cyanide ion.

24. 24
2. Reaction with electrophiles
- for example
 Nitration
 Sulfonation
 Halogenation

25. 25
3. Substitution reaction
Substitution at nitrogen:
A) Metallation of Pyrrole

26. 26
B) Formation of N-substituted pyrrole

27. 27
Derivatives of pyrrole
6.

28. 28
 The functional derivatives of pyrrole is
1. Hydroxypyrroles :
Pyrroles with hydroxyl groups on carbon side chains can be made
by reduction of the appropriate carbonyl compound with
hydrides, by Grignard synthesis, or by insertion of ethylene
oxide or formaldehyde. For example, pyrrole plus formaldehyde
gives 2-hydroxymethylpyrrole. The hydroxymethylpyrroles do
not act as normal primary alcohols because of resonance
stabilization of carbonium ions formed by loss of water.
2-hydroxymethylpyrrole

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2. Aldehydes and Ketones:
 Pyrrole aldehydes and ketones are somewhat less reactive
than the corresponding benzenoid derivatives.
 They react with pyrroles under acidic conditions to form
dipyrrylmethenes.
dipyrrylmethenes

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3. Pyrrole Carboxylic Acids and Esters:
 The acids are considerably less stable than benzoic acid and often
decarboxylate readily on heating.
 However, electron-withdrawing substituents tend to stabilize
them toward decarboxylation. The pyrrole esters are important
synthetically because they stabilize the ring and may also act as
protecting groups.
 Thus, the esters can be utilized synthetically and then hydrolyzed
to the acid, which can be decarboxylated by heating.
 Often β-esters are hydrolyzed more easily than the α-esters.

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4. Vinyl Pyrroles:
 Reaction between ketoximes and acetylene in an alkali metal
hydroxide–dimethyl sulfoxide (DMSO) system havemade vinyl
pyrroles.
 The 1-vinylpyrroles are highly reactive and are sensitive to
oxygen. Conjugation of the vinyl group with the aromatic ring leads
to a greater susceptibility to electrophilic attack.
Vinyl Pyrroles
Vinyl

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 Pyrroles can be condensed to compounds containing two, three,
or four pyrrole nuclei. These are important in synthetic routes.
5. Condensed Pyrroles:
6. Bipyrroles:

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7.
Synthesis of Pyrrole

34. 34
1. Knorr Synthesis:
 Condensation of an α-aminoketone with a carbonyl compound was
first reported by Knorr.
 This reaction and its modifications are among the most important
and widely used methods for the synthesis of pyrroles.
α-aminoketone β-dicarbonyl derivative
pyrrole

35. 35
RO2C
O
R2
R3 O
HN
R4
R5
Base
RO2C
O
R2
R3 O
HN
R4
R5
N
R5
HO
R2
H
R4
OH
R3
H
RO2C
-2H2O
N
R5
R4
R2
RO2C
R3
Can be removed;
hydrol., decarbox.
Alkyl,
aryl
May be H
If R2=CO2R
Can be removed;
hydrol., decarbox
Mechanism

36. 36
2. Hantzsch and Feist Syntheses:
 The Hantzsch synthesis of pyrroles involves condensation of an α-
haloketone with a β-keto ester in the presence of ammonia or an
amine.
α-haloketone β-keto ester
pyrrole

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Step I
Step II
Mechanism

38. 38
3. Paal-Knorr Pyrrole Synthesis
 Generally Substituted pyrrole may be synthesized through the
cyclization of 1,4-diketones in combination with ammonia (NH3) or
amines.
The ring-closure is proceeded by dehydration (condensation),
which then yields the two double bonds and thus the aromatic π
system.
The formation of the energetically favored aromatic system is
one of the driving forces of the reaction.

39. 39
Mechanism
1,4-diketones pyrrole

40. 40
4. Pyrrole is obtained by distillation of succinimide over zinc
dust

41. 41
5. By heating a mixture of furan, ammonia and steam over
alumina catalyst

42. 42
6. By passing a mixture of acetylene and ammonia over
red hot tube.

43. 43
The reaction of a nitroalkene with an α-isocyanoacetate under
basic conditions.
7. Barton-Zard Pyrrole Synthesis
nitroalkeneα-isocyanoacetate
Pyrrole

44. 44
Mechanism

45. 45
Applications
8.

46. 46
 Pyrrole is essential to the production of many different
chemicals.
 N-methylpyrrole is a precursor to N-methylpyrrolecarboxylic
acid, a building-block in pharmaceutical chemistry.
 Although there is a claim that pyrrole is used as an additive to
cigarettes, it is typically listed as a constituent of tobacco
smoke and not as an ingredient.
 Pyrrole is also use in commercial and pharmaceuticals.

47. 47
 Pyrrole subunit has diverse applications in therapeutically
active compounds including fungicides, antibiotics, anti-
inammatory drugs,cholesterol reducing drugs, antitumor agents
and many more.
 for example Pyrocyclidine act as anti-muscarinic agent use in
the treatment of parkinsonism.
Pyrocyclidine

48. 48
References
9.

49. 49
1. Morrin Acheson: An Introduction to The Chemistry of
Heterocyclic Compounds, Wiley student edition, Third
edition,2008, 89-113.
2. Thomas Gilchrist: Heterocyclic Chemistry, Pearson education,
Third edition,2007, 12, 192-205.
3. Raj Bansal: Heterocyclic Chemistry, New age international
publishers, Fifth edition, 2012, 1-8, 152-177.
4. Joule and Mills: Heterocyclic Chemistry, Blackwell Publishing,
Fourth edition, 2008, 237.
5. Dr. Mukherjee K. S.:Textbook of Organic Chemistry, NCBA,
Third edition, 2010, 440-448.

50. 50
6. Tewari K. S., Vishnoi N. K.: A Textbook of Organic Chemistry,
Vikas publishing house, Second edition, 2004, 1025-1029.
7. Ghosh S. K.: Advaced General Organic chemistry- A Modern
Approch Part II, NCBA, Third edition, 2013, 1105-1113.
8. Solomons and Fryhle: Organic chemistry, Wiley student edition,
Eighth edition, 2007, 644.
9. Fabio Bellina and Renzo Rossi: Synthesis and biological activity
of pyrrole, pyrroline and pyrrolidine derivatives with two aryl
groups on adjacent positions, Elsevier Ltd,2006 , 7213–7256.
10. Varun Bhardwaj: Pyrrole: a resourceful small molecule in
keymedicinal hetero-aromatics, The Royal Society of Chemistry
, 2015, 15233.

51. 51
11. Shrinivas Joshi, U. More: Pyrrole: Chemical synthesis,
microwave assisted synthesis, reactions and applications: A
review, Article in current organic chemistry 17:2279-
2304 · January 2013.
12. Pragi arora, varun arora , H.S. Lamba and deepak wadhwa:
Importance Of Heterocyclic Chemistry: A Review, IJPSR,
2012; vol. 3(9): 2947-2954 .
13. Dr. Usha Yadav 1 and Dheeraj Kumar2: Study Of
Heterocyclic Compound – Pyrrole (IJRST) 2015, Vol. No. 5,
Issue No. I, Jan-Mar , ISSN: 2249-0604 .

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Thank
you