Heterocyclic - PSAU · Pyrrole, furan and thiophene are colorless liquids of boiling points 126o,...
Transcript of Heterocyclic - PSAU · Pyrrole, furan and thiophene are colorless liquids of boiling points 126o,...
Heterocyclic Chemistry
N
O
SFive-membered Heterocycles
Pyrrole, Furan and Thiophene
1-To identify Types of five member of Heterocyclic
compounds
2- To Know Sources of five member of Heterocyclic
compounds
3- To Know syntheses of five member of
Heterocyclic compounds
4-To understand methods of reaction five member of
Heterocyclic compounds
Hetero-Monocyclic Compounds
The main reason for the study of pyrrole came from the work on
the structure of haem; the blood respiratory pigment, and the
chlorophyll; the green photosynthetic pigment of plants.
Thiophen does occur in plants in association with polyacetylenes
with which they are biogenetically closely linked.
Furan occurs widely in secondary plant metabolites, especially in
terpenoids.
Unsubstituted pyrrole, furan, and thiophene are usually obtained
from petroleum
N
H
S O
Pyrrole
Thiophene Furan
A. Five-membered Rings with one Heteroatom
X
X = NH Pyrrole
= O Furan
= S Thiophene
Pyrrole, furan and thiophene are colorless liquids of boiling points
126o, 32o, and 84o respectively.
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.
N N N
H H H
N
H
N
H
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Structure and Aromaticity
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),
nitrogen (3.04) and thiophene (2.56).
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
2) They tend to react by electrophilic substitution due appearance of –ve charge
on carbon 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 HeteroatomStructure and Aromaticity
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomStructure and Aromaticity
X
X = NH Pyrrole
= O Furan
= S Thiophene
3-Their protons show the same sort of chemical shift in NMR
as the protons of benzene with δ = 6.5 ppm-8 ppm
2- Electrons not available for
protonation—hence not basic
3- 6 electrons over 5 ring atoms …..
Electron rich… so more reactive than
benzene towered electrophilic
substitution
Pyrrole > Furan >Thiophene>benzene
4-Their protons show the same sort of chemical shift in NMR
as the protons of benzene with δ = 6.5 ppm-8 ppm
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomStructure and Aromaticity
3-Their protons show the same sort of chemical shift in NMR
as the protons of benzene with δ = 6.5 ppm-8 ppm
2- Electrons not available for
protonation—hence not basic
3- 6 electrons over 5 ring atoms …..
Electron rich… so more reactive than
benzene towered electrophilic
substitution
Pyrrole > Furan >Thiophene>benzene
4-Their protons show the same sort of chemical shift in NMR
as the protons of benzene with δ = 6.5 ppm-8 ppm
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomStructure and Aromaticity
4- The pattern of reactivity with Electrophilic reagents. Cycloalkanes
…… by addition reaction
Aromatic compounds ……. By substitution
addition followed by proton loss
[ onium intermediate
Order of reactivity :Pyrrole > Furan >Thiophene>benzene
X
X X X
X X X
X
+ E+
H
E
HE
H
EE
- H+
HE
HE
E
- H+
C2-attack
C3-attack
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomStructure and Aromaticity
5-The order of aromaticity
Thiophene > Pyrrole > Furan
ne
In case of Thiophene [S] donate & accept
electrons…… so
delocalization as complete as benzeneS
In case of Furan [O] electronegativity more …. Diene-like
character CH2=CH-CH=CH2 O
In case of Pyrrole [N] -Diene-like character
CH2=CH-CH=CH2
Evidences of aromatic character in pyrrole
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
NH
NNNN
-H+
Pyrrole anion( Conjugated base)
1) All ring bonds are intermediates between
single and double bonds.
2) It tends to react by electrophilic substitution
NH
NH
PyrrolidinePyrrole
Dipole monent of
pyrrole and its saturated analog
NH
Pyrrole
aroamtic 2 amine
NH
Pyrrolidin
Aliphatic 2 amine
<
Basicity of pyrrole and its saturated analog
°°
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
thus the dipole moment of pyrrole compared with pyrolidine is reverted and thus
protonation occurs at carbons not at N
NH
N+
N N
CH3
H2
K+
Cl-
+ KICH3I
HCl
KOH
H2O +
3) Its exceptional lack of basicity and strong acidity as a secondary amine compared to
the aliphatic analog (pyrrolidine). This can be explained on the basis of participation of
N lone pair in aromatic sextet (see the resonance structures)
NH
N-Na
+ NaNH2Liq NH3
strong baseweak acid salt
NH
NNNN
-H+
Pyrrole anion( Conjugated base)
So Its weak acid
not basic as the
secondary amines
Lone pair of N is
involved in cloud
and not
Available for
sharing with acids
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Sources & Synthesis
Pyrrole & Thiophene …. Coal Tar
Pyrrole ring ….
Prophyrin system…..
Chlorophyll &
Hemoglobin
Furan ….. Decarbonylation of
Furfuraldehyde …….
Oat hulls, corn cobs or rice hullsOat hulls corn cobs rice hulls
A) Sources
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomB) Synthesis
ThiopheneCH3-CH2-CH2-CH3 + 4 S
S
560+ 3 H2S
n- butane
Pyrrole
HC CH + 2 HCHOCu2C2 HOH2CC CCH2OH
NH
NH3
pressure
1,2-butyldiolFormaldehydeEthyne
Furan ( C5H8O4 )nH2O,H+
CHO
(CHOH)3
CH2OH
Pentose
OCHO
OFurfural Furan
-3H2O400
Pentosan
Reactions of pyrrole
NH
NH
NH
NH
NH
NH
OHCCOCH3
CO
C
O
O
H3C
H3CAc2
O
1- DMF/POCl3
2- H2 O + Na
2 CO3
CH
3 CO
O-N
O2 +
NO2
H2 \pt
AcOH\200
SO 3
pyridine
HO3S
2-nitropyrrole
pyrrolidine2-pyrrole sulfonic acid
2-acetylpyrrole
pyrrole-2-carboxaldehyde
acetic anhydride
Acetylation
Vilsmier Rex
Nitration
ReductionSulfonation
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
HNO3
+Ac2o
NH
:CCl2
HCCl3 / NaOH NH
CCl
Cl
ring openning
enlargementN
Cl
3-chloropyridine
with carbine
Halogenation
X
Br2
Dioxane
SOCl2
pyridine
X
X
Br
Cl
2-bromo.....
2-chloro.....
Reactions of pyrrole A. Five-membered Rings with one Heteroatom
Hetero-Monocyclic Compounds
O
O
OO
O
OHCCOCH3Ac2
O
1- DMF/POCl
3
2- H2 O + Na
2 CO3
dil NH
O3
CH3C
OO
H,[0]
NO2
SO 3 ,100
pyridine
HO3S
2-nitrofuran2-furan sulfonic acid
2-acetyl furae
furfulaldehyde furfural BF3
NitrationSulfonation
Acetylation
Vilsmier Rex
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomReactions of Furan
Rex of furfural
O
OCOOH
OO
CH3CH2OH
+
NaOH
30 c
CO
H
N2 H
2base2-methyl furan
+ Furfu
ral
KCN
OC
O
CH
OH
O
furoin
[O]
OC
O
C
O
O
furil
O CHO COOH
O
furfulic acid
NaOH
Cannizaro RexWolff-Kishner
reduction
Benzoin-
condensation
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Reaction of Thiophene
S
S
S
SCOCH3CH3COCl
dil NHO
3C
H3C
OO
H,[0]
NO2
SO3 , 100pyridine
HO3S
2-thiophene-2- sulfonic acid
SOCL4
SNO2O2NHNO3
SS
S S S
BrBr
Br
Cl ClCl
Cl
Cl Cl
Cl
Br 2
AcOHCl2
50
major minor
Nitration
Sulfonation
Acetylation
Halogenation
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Five Membered Heteroaromatic Rings
Containing 2X , at least one nitrogen
X
N
X
N
X = S ,O ,or N
1,3-Azoles 1,2-Azoles
Thiazole [ 1,3-thiazole]
Oxazole [ 1,3-oxazole]
Imidazole [ 1,3-diazole]
Isothiazole [ 1,2-thiazole]
Isoxazole [ 1,2-oxazole]
Pyrazole [ 1,2-diazole]
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
NH
N
Imidazole
Aromaticity & Bascisity
Strong base, due to the greater electron releasing capacity of the two nitrogen's
NH
N
2ry amine
3ry amine
NH
N H
N
N H
H
3ry amine ismore basic than 2ry amine
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Five Membered Heteroaromatic Rings
Containing 2X , at least one nitrogen
N
N
H
Pyridine like nitrogen( basic character )
Pyrrole like nitrogen( involved in aromaticity)
Importance of the ring
Building blockes as Histidine and Histamine
It exist in two tautomeric forms …..
As base & weak acid
NH
N
N
NH
50 % 50 %
Fused Five Membered
Heteroaromatic Rings With one X
NH
NH
benzo[b]pyrroleIndole
benzo[c]pyrroleIsoindole
Found in coal tar & orange blossoms, humane feces
In amino acids as Tryptophan, alkaloid * pigments
NH
CH2CH
COOH
NH2
Tryptophan
NH
Carbazole
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Fischer Synthesis NHNH2
+C
O
CH3
Ph
Phenylhydrazine acetophenon
NHN
CH3
Ph
NH
Ph
2-phenyl indole
AcO
H
or ZnC
l 2
- H2O
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Indole
Fused Five Membered
Heteroaromatic Rings With one X
Basicity of Indole
Not basic because lone pair is delocalized
and contributed to the Aromatic system
It undrego Electrophilic
Subistitution at Position 3
NH
+ E+
NH
NH
NH
NH
H
E
HE
H
E
H
E
Not favoureddestroy aromatic str.of benzene
C-3attack
C-2attack
Hetero-Monocyclic Compounds
A. Five-membered Rings with one HeteroatomFused Five Membered
Heteroaromatic Rings With one X Indole
- H+
- H+
attack at C-2
attack at C-3
three resonance structures more stable
two resonance structures less satble
Not formed
Rex with carbene
Vilsmier Rex
NH
DMF / POCl3
tolueneNH
CHO
Indole-3-carboxylaldehyde
NH
:CCl 2
(HCCl 3
/NaOH)
:CHCl(H2 CCl
2 /NaOH)
N
Cl
Cl
HN
Cl
N
Cl
H
HN
3-chloroquinoline
quinoline
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
Fused Five Membered Hetero aromatic Rings
With tow X
NH
N
Benzimidazole
In nature as N-ribosyl-dimethyl
benzimidazole …
In Vit B12 :Commercially as an parasisticide
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom