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Home , Pyrrole, Thiophene

Heterocyclic Chemistry

By Dr. Mohamed Abd Ellatif Zein Assistant Professor Chemistry Department Faculty of Science Heterocyclic Chemistry Heterocyclic Chemistry

N Five-membered Heterocycles S O , and 1-To identify types of five membered heterocyclic compounds 2- To know sources of five membered heterocyclic 3-To know syntheses of five membered heterocyclic compounds compounds 4-To understand chemical reactions of five membered heterocyclic compounds Hetero-Monocyclic Compounds A. Five-membered Rings with one Heteroatom

 The main reason for the study of pyrrole came from the work on the structure of haem; the blood respiratory pigment, and the ; the green photosynthetic pigment of plants.  Thiophene and its derivatives occurs in .  Furan occurs widely in secondary plant metabolites, especially in terpenoids.  Unsubstituted pyrrole, furan, and thiophene are usually obtained from petroleum.

X = NH Pyrrole

= O Furan N S O X H Thiophene Furan = S Thiophene Pyrrole Hetero-Monocyclic Compounds A. Five-membered Rings with one Heteroatom

 Pyrrole, furan and thiophene are colorless liquids of boiling points 126o, 32o, and 84o respectively.  Pyrrole has a relatively high as compared to furan and thiophene, this is due to the presence of intermolecular bonding in pyrrole.

N N N N N H H H H H Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Structure and

 Pyrrole furan and thiophene are aromatic because: 1) they fulfill the criteria for aromaticity, the extent of delocalization of the nonbonding electron pair is decisive for the aromaticity, thus the grading of aromaticity is in the order of: Furan < Pyrrole < Thiophene < Benzene this order is consistent with the order of electronegativity values for oxygen (3.44), The order of aromaticity (3.04) and thiophene (2.56). > Thiophene > Pyrrole > Furan Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Structure and Aromaticity

2) They tend to react by electrophilic substitution due appearance of –ve charge on atoms due to delocalization as shown in the following resonance structures

O O O O O

S S S S S

N N N N N H H H H H Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Structure and Aromaticity

3- Electrons not available for protonation—hence not basic X = NH Pyrrole 4- 6  electrons over 5 ring atoms ….. Electron rich… so more reactive than = O Furan benzene towards electrophilic X substitution. = S Thiophene The order of reactivity is: Pyrrole > Furan > Thiophene > Benzene Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Structure and Aromaticity

5- The pattern of reactivity with Electrophilic reagents. Aromatic compounds ……. By substitution addition followed by proton loss [ onium intermediate ] Order of reactivity : Pyrrole > Furan > Thiophene > Benzene

H + H H - H E E E E C2-attack X X X X

+ E+ X H H E E E + C3-attack - H

X X X Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Structure and Aromaticity ne 6-The order of aromaticity

Benzene > Thiophene > Pyrrole > Furan

In case of Thiophene [S] donate & accept electrons…… so delocalization as complete as benzene S

In case of Pyrrole [N] --like character

CH2=CH-CH=CH2

In case of Furan [O] electronegativity more …. Diene-like character CH =CH-CH=CH 2 2 O Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Evidences of aromatic character in pyrrole It tends to react by electrophilic substitution

-H+

N N N N N H Pyrrole anion ( Conjugated base) Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom 3) Its exceptional lack of basicity and strong acidity as a secondary compared to the aliphatic analog (). This can be explained on the basis of participation of N lone pair in aromatic sextet (see the resonance structures) So Its weak acid HCl -H+ + not basic as the N N Cl- N N N N N H H H2 secondary Pyrrole anion ( Conjugated base) KOH Lone pair of N is involved in  cloud Liq NH3 + NaNH2 and not H2O + CH3I + KI N N H -Na Available for N N + sharing with acids K CH3 weak acid strong base salt thus the dipole moment of pyrrole compared with pyrolidine is reverted and thus protonation occurs at not at N

Dipole monent of Basicity of pyrrole and its saturated analog pyrrole and its saturated analog < N N N N H H H H Pyrrole Pyrrolidin Pyrrole Pyrrolidine aroamtic 2° amine Aliphatic °2 amine Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Sources & Synthesis A) Sources Pyrrole & Thiophene …. Tar

Pyrrole ring …. system….. Chlorophyll &

Furan ….. Decarbonylation of Furfuraldehyde ……. Oat hulls, corn cobs or rice hulls Oat hulls corn cobs rice hulls Hetero-Monocyclic Compounds

B) Synthesis A. Five-membered Rings with one Heteroatom

Thiophene 560 CH3-CH2-CH2-CH3 + 4 S + 3 H2S S n-

Cu2C2 HC CH + 2 HCHO HOH2CC CCH2OH Ethyne Formaldehyde 1,2-butyldiol NH3 Pyrrole pressure

N H CHO Furan H O,H+ -3H O 400 ( C5H8O4 )n 2 (CHOH)3 2 CHO CH2OH O O Pentosan Pentose Furfural Furan Hetero-Monocyclic Compounds

Reactions of pyrrole A. Five-membered Rings with one Heteroatom

1- DM O F/P 2- O H Cl H3C C OHC 2 O 3 N + O Na c O COCH H 2 CO A 2 3 N H3C C pyrrole-2-carboxaldehyde 3 H O 2-acetylpyrrole acetic anhydride N H 2 \ H pt A Vilsmier Rex O 3 ne C cO i H S id H yr 3 \ C 2 p HNO3 0 Acetylation O 0 +A O c o -

2 N HO3S N N O H H 2 + 2-pyrrole sulfonic acid pyrrolidine

NO2 N H Sulfonation 2-nitropyrrole Reduction

Nitration Hetero-Monocyclic Compounds

Reactions of Pyrrole A. Five-membered Rings with one Heteroatom with Cl C Cl Cl :CCl2 ring openning

N HCCl3 / NaOH N enlargement H H N 3-chloropyridine

Br2 Dioxane Br Halogenation X 2-bromo.....

X

SOCl2 Cl X 2-chloro..... Hetero-Monocyclic Compounds

Reactions of Furan A. Five-membered Rings with one Heteroatom

Acetylation

1- DM OHC F/P O 2- OC H l O COCH3 2 O 3 Ac2 + N O furfulaldehyde a C 2 O BF3 furfural 3 2-acetyl furae Vilsmier Rex

di O l N H C O 0 H 3 10 3C , O O 3 ne O S idi H yr ,[ p 0] NO2 HO S O 3 O

2-furan sulfonic acid 2-nitrofuran Sulfonation Nitration Hetero-Monocyclic Compounds

Reactions of Thiophene A. Five-membered Rings with one Heteroatom

Sulfonation Acetylation Cl 3CO COCH3 S CH O L S 3 1 C 4 HO3S py , 00 SO S rid ine

2-thiophene-2- sulfonic acid S di l N H C O H 3 3C r 2 O Nitration B O H H ,[ O 0] Ac Cl2 NO2 50 S HNO3 O N NO Br 2 S 2 Br S Br S major minor Cl Cl

Cl Cl Cl S Cl S Cl S

Halogenation Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Five Membered Heteroaromatic Rings Containing 2X , at least one nitrogen

N

N

X X X = S ,O ,or N

1,3-Azoles 1,2-Azoles

Thiazole [ 1,3-thiazole] Isothiazole [ 1,2-thiazole]

Oxazole [ 1,3-] [ 1,2-oxazole]

Imidazole [ 1,3-diazole] Pyrazole [ 1,2-diazole] Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom

Five Membered Heteroaromatic Rings Containing 2X , at least one nitrogen N

N Aromaticity & Basicity H Strong base, due to the greater electron releasing capacity of the two nitrogen's

Pyridine like nitrogen 3ry amine N ( basic character ) N H H N N

N N N H N H H 2ry amine H Pyrrole like nitrogen 3ry amine ismore basic than 2ry amine ( involved in aromaticity)

Importance of the ring N NH

Building blocks as Histidine and Histamine It exist in two tautomeric forms ….. N N H 50 % 50 % Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Fused Five Membered Heteroaromatic Rings With one X

NH

N H benzo[b]pyrrole benzo[c]pyrrole

NH2

CH2CH COOH N N H H Tryptophan Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom Fused Five Membered Heteroaromatic Rings With one X Indole

CH CH + 3 3 C - H2O O Fischer Synthesis NHNH Ph 2 NHN Ph Phenylhydrazine acetophenon

H O l 2 c nC A Z or

N Ph H 2-phenyl indole Basicity of Indole Not basic because lone pair is delocalized and contributed to the Aromatic system Hetero-Monocyclic Compounds

Fused Five Membered A. Five-membered Rings with one Heteroatom Heteroaromatic Rings With one X Indole

It undrego Electrophilic - H+ attack at C-2 Subistitution at Position 3 three resonance structures more stable

- H+ attack at C-3 Not formed two resonance structures less satble

H H C-2 attack N E N E H H Not favoured destroy + E+ aromatic str. of benzene N H C-3 attack H H E E

N N H H Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom

Vilsmier Rex CHO DMF / POCl3

toluene N N H H Indole-3-carboxylaldehyde

Cl Cl Cl

l 2 N CC H) : aO N /N H l 3 CC (H 3-chloroquinoline

: CH N C H (H l 2 C Reaction with carbene Cl 2 /N aO Cl H ) H

N N H quinoline Hetero-Monocyclic Compounds

A. Five-membered Rings with one Heteroatom

Fused Five Membered Hetero aromatic Rings

With two X N

N … H Benzimidazole In Vit B12 : Commercially as an parasiticide