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A Seminar On

“Organic Chemistry of Five Membered Hetrocyclic Compound :

Pyrrole”Submitted To

SAVITRIBAI PHULE PUNE UNIVERSITY, PUNEBy

Ms. Bhalekar Pournima AshokM Pharm Sem I

(Department Of Pharmaceutical ChemistryRoll 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)

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Contents

• Introduction: heterocyclic compounds

• Introduction: pyrrole

• Nomenclature

• Physical properties

• Chemical properties/ reaction

• Derivatives of pyrrole

• Synthesis of pyrrole

•Application

• References

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Introduction: Heterocyclic Compounds

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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.

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Classification of Heterocyclic compounds

5- Membered heterocyclic compounds

One heterotom:Example-furone

pyrrole

More than one heteroatom:

Example- PyrazoleImidazoleOxazole

6-Membered heterocyclic compounds

One heteroatomExample- Pyridine,

piperidine

More than one heteroatom:

Example- pyrimidine

7-Membered heterocyclic compounds

Example: Oxepine

Condensed heterocyclic compounds

Example: Indole, Quinoline

Isoquinoline

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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

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7-Membered heterocyclic compounds

1-H-Azpine Oxepine

Condensed heterocyclic compounds

Quinoline Isoquinoline

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Introduction: Pyrrole

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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 AndersonObtained 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

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In naming pyrrole and its derivatives, the nitrogen atom is assigned position-1.

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5 α‘

β’ β

α

The position of the substituent may be specified in Arabic numerals or in Greek letters.

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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

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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.

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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 .

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Chemical properties/ Reaction

5.

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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

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Basicity

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

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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

NH

H2

NH2OH

-H

NH

H2

NHOH

H

NH NOH

H

-H

HNNOH

NH2OH

-NH3HON NOH

succindialdehyde dioxime

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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.

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2. Reaction with electrophiles

- for example Nitration Sulfonation Halogenation

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3. Substitution reaction

Substitution at nitrogen: A) Metallation of Pyrrole

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B) Formation of N-substituted pyrrole

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Derivatives of pyrrole

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The functional derivatives of pyrrole is1. 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 PyrrolesVinyl

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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

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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

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RO2C

OR2

R3 O

HNR4

R5

Base

RO2C

OR2

R3 O

HNR4

R5

N

R5

HO

R2

H

R4

OH

R3

HRO2C

-2H2O

N

R5

R4

R2

RO2C

R3

Can be removed;hydrol., decarbox.

Alkyl,aryl

May be HIf R2=CO2RCan be removed;hydrol., decarbox

Mechanism

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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

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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.

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Mechanism

1,4-diketones pyrrole

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

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

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

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The reaction of a nitroalkene with an α-isocyanoacetate under basic conditions.

7. Barton-Zard Pyrrole Synthesis

nitroalkene α-isocyanoacetatePyrrole

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Mechanism

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Applications

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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.

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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

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References

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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.

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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.

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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