Post on 21-Dec-2015
Aromaticity of heterocyclic compounds
Characteristics of aromatic compounds:
1.The structure must be cyclic with conjugated π bonds.
2.All atoms must be sp2 hybridized (i.e. double bond, cation or anion)
3.The compound must follow Hückel's Rule (4n + 2) π, where n = 0, 1,
2, 3, and so on).
4. Coplanar structure, with all the contributing atoms in the same
plane.
Antiaromatic compound: They are cyclic, conjugated, with
sp2 orbitals and follows 4n rule.
Nonaromatic compound: All atoms are not sp2 hybridized.
NNH
NNH
NH
N
Aromatic compounds
cyclic, conjugate
Sp2
6 pi electrons (4n+2 rule)
planar
cyclic, conjugate
Sp2
10 pi electrons (4n+2 rule)
planar
cyclic, conjugate
Sp2
2 pi electrons (4n+2 rule)
planar
cyclic, conjugate
Sp2
14 pi electrons (4n+2 rule)
planar
Antiaromatic compounds
cyclic, conjugate
Sp2
4 pi electrons (4n rule)
planar
Nonaromatic compounds
Have separate sp3 atoms
(i.e not all atoms are sp2)
cyclic, conjugate
Sp2
8 pi electrons (4n rule)
planar
HN
The π-excessive heterocyclic compoundsThey are Planar, fully conjugated, monocyclic systems with
6electrons [i.e. follow (4n + 2) electrons ,(n is an integer 0, 1, 2,
etc.)]
In benzene each carbon corner has one unit of pi-electron, but this system
(-excessive) has in each corner more than one -electron.
As a result of such a situation these molecules are generally more reactive
toward electrophiles than benzene itself and generally have reactivity similar
to that of electron rich benzene derivatives e.g. phenol or aniline.
O NH
S
16 21 29R.E.
In terms of valence bond theory these compounds are
resonance hybrids. However, resonance structures
have charge separation.
X X X X X
X = O, N, S
The π-difficient heterocyclic compounds
They are Fully unsaturated six membered heterocycles, the heteroatom lone
pair of electron does not contribute to this electronic configuration, in fact it is
out of plane.
As a result the reactivity pattern toward electrophiles similar to that of -
deficient benzene derivatives e.g. nitrobenzene.
Moreover, having p-deficient carbon these molecules are reactive towards
nucleophiles.
N N N N N
Kekulé forms
Reactivity of Five membered pi-Excessive Heterocyclic ring
Reactivity towards electrophilic substitution
Pyrrole, furan and thiophene are all much more reactive than benzene toward electrophilic substitution.
NH
OS
furan pyrrolethiophenebenzene
Thiophene is 100 times more reactive than benzene and pyrrole is the most reactive. Furan is less reactive than pyrrole because oxygen is more electronegative than nitrogen.
There are two position for electrophilic attack, C-2 and C-3.
Attack at C-2 is preferred because it yields a more stable
carbocation (3 resonance structures, while attack at C-3 gives
only 2 resonance structures(
E+ substitution occurs predominately at the 2-position (and if that
position is already substituted, substitution occurs at the C-5).
If 2- and 5-position are already occupied, electrophilic
substitution takes place at 3-position.
X
X = NH, O, S
attack at C-2
attack at C-3
X
X
X
E
H
E
H
E
H
XX X
E E
H
E
H
X E
-
H-
E
Resonance
energy 21 Kcal/mol 16 Kcal/mol 25 Kcal/mol
Reactivity sequence
N
H
O S
Although furan is the least aromatic (R.E. = 16 Kcal / mol), pyrrole (R.E.
= 21 Kcal / mol) is most reactive. Thiophene which is the most aromatic
with (R.E. = 29 Kcal / mol) is least reactive in electrophilic reactions.
This inverted reactivity pattern is due to the excessive participation of
nitrogen lone pair is stabilising reactive intermediate for substitution at C-2.
Energy needed to go from the more aromatic pyrrole to its reactive
intermediate is less than energy needed for a similar step with furan
N
H
O
E
E
N
H
E N
H
E
O E O E
Less energy demand
1- It was found that pyrrole reacts readily with some weak
electrophiles, while thiophene and furan did not react
NH
ClAr N N
Mannish reaction
ArCHO / R2NH
NH
N
NAr
NH
N
Ar
R
R
O
S
ClAr N N
Mannish reaction
No reaction
2- Halogenation. Just as is true for aniline, the pyrrole ring is
reactive toward bromine or chlorine, giving polysubstituted products
NH
Br2
NH
Br Br
BrBr
O
Br2
CS2, -5 oC OBr O
Br
Br
OBrBr
OBr
heat
- HBr
3- On the other hand, Due to the low aromaticity of furan, it reacts
differently towards bromine
4. Due to the sensitivity to acids nitration is conducted in
aprotic media.
NH
CH3CONO3
- 10 oC NH
NO2 NH
NO2
+
Major (50 %) Minor (13 %)
5- Only thiophene (least acid reactive can be nitrated by
mixed acid nitration.
S
HNO3
SNO2
S
NO2
+
Major Minor
H2SO4
6 : 1
6-Due to the low aromaticity of furan, its reactions in presence of a
nucleophile gives in many cases adducts in which intermediate
instead of undergoing proton loss reacts with nucleophile, e. g.
O
HNO3
Ac2O, -5 oCO
NO2
heat
ONO2 O
NO2AcO
AcO
ONO2
- AcOH
7. Acylation of -excessive molecules can be made either in complete
absence of a Lewis acid or in presence of ZnCl2. Pyrrole is acylated at N
and not at C-
NH
Ac2O
AcONaN
COCH3
N
Ac2O
H2O NH
MgBrO
CH3
Furan and thiophene undergo Friedel –Craft
reaction while pyrrole did not?
O
Ac2O
AcONa O
S
Ac2O
ZnCl2 S
O
CH3
O
CH3
O
Cl2 in CH2Cl2
O Cl
Br2 in Dioxan
-5oC O Br
HNO3 fuming
Ac2O / -5oC OAcO NO2 O NO2
SO3 / pyridine
O SO3H
O COCH3
(CH3CO)2O
BF3 / 0oC
Reactions of Furan
S
S I
S Br
S NO2 S
S SO3H
S COCH3
Ac2O / SnCl4
or ZnCl2
I2
NO O
Br
HNO3 / H2SO4+
NO2
6 : 1
H2SO4
room temp
(95%)
Reactions of Thiophene
NH
NH
X
NH
N=NPh
NH
NO2 NH
NH
SO3H
N
Ac2O
X2
+
NO2
50 % :13%
SO3 / pyridin
XX
X
CH3CONO3
- 10 oC
PhN2Cl+ -
COCH3
CH2O / R2NH
NH
CH2NR2
Reactions of Pyrrole
Unlike furan and thiophene, pyrrole is weakly acidic in nature.
Thus, on reaction with metallic potassium or potassium hydroxide it
forms a potassium salt, which is hydrolyzed back to pyrrole on
treatment with water.
NH
KOH
N
K
+ H2O
Acidic character of pyrrole
Pyrrole is a resonance hybrid of various structures carrying a positive charge on nitrogen.
The greater stability of pyrrole anion compared to
pyrrole.
The acidic character of pyrrole is due to
The higher stability of the anion is due to resonance.
N N NN
NH
N.. + H+
The acidic character is also reflected in the formation of pyrrolyl
magnesium halide when reacted with alkylmagnesium halide.
N
K
RX
N
R
N
H
R
N
MgBr
-
+
CO2
N
H
COOH
N
H
COR
RCOCl
The action of acids pyrrole, thiophene and furan
NH
HCl
NH
NH
NH
H
H
H
H
S
H3PO4
S S
S
O
H
OH
H2OOHC CHO
trimerization
trimerization
12
34
5
12
3 4
5
The mechanism of trimerization of
pyrrole in acid medium
NH
HCl
NH
H
H
NH
NH
NH
NH
NH
HCl
NH
NH
NH
H
H
H
H
H
H
We have seen that the reactivity of pyrrole, furan and thiophene towards electrophilic substitution is in the following order
NH O S
The reactivity of these rings towards nucleophilic substitution is
in the opposite order
NH O S
Nucleophilic Substitutions in
Pyrrole, Furan and Thiophene
Pyrroles: the pyrrole ring is the least reactive and both 2-
halo- and 3-halopyrroles behave like aryl halides in
nucleophilic displacement. Thus, 2-chloropyrrole does not
react with potassium tert-butoxide or with lithium aluminum
hydride
NH
Cl
KOC(CH3)3
LiAlH4
No reaction
No reaction
X Br
X = O, S
: Nu
X Br
NuX Nu
- Br
O Br
HN
200oC O N
Furans are more reactive towards nucleophilic displacement than pyrrole. 2-bromo- and 2-chloro react with piperidine at 200oC as follows:
The presence of electron-withdrawing groups on the furan
ring facilitates nucleophilic displacement. Thus, 2-bromo-5-
nitrofuran and methyl 2-bromo-5-carboxylate react readily
with nucleophiles
O BrO2N
HN
25oC O NO2N
O BrH3CO2C
HN
20oC
NaOCH3
CH3OH / 20oC
O NH3CO2C
O OCH3H3CO2C
•It is of considerable interest that in these reactions the
furans react about 10 times faster than the corresponding
benzene analogues. This strong behavior has also been
observed in theiophene series
Thiophenes
Nucleophilic substitution occurs much more readily within the
thiophene series than it does for the corresponding benzene
compounds. The thiophenes are at least 1000 times more
reactive than corresponding benzene analogues (This increased
reactivity has also been noticed in the electrophilic substitution of
thiophenes compared to the corresponding benzene analogues) .
The increased reactivity of thiophene ring nucleophilic
substitution can be explained by Wheland intermediates involved
in nucleophilic substitution of bromine in 2-bromo-5-
nitrothiophene.
It is suggested that the sulfur atom causes additional
stabilization by involvement of its d-orbitals "Structure III"
S BrO2N
Nu
S BrO2N
Nu
IS
N
O
O
Br
Nu
II
III
SN
O
O
Br
Nu
SN
O
O
Br
Nu
IV
It must be noted that the lone pair of the sulphur atom also enters into
resonance with the electrons. X-ray studies indicate that the valency
angle of C-S-C in thiophene is nearly 91o and not 105o as expected.
This can be explained by assuming that the 3d orbital of sulphur are
also used in resonance and following additional contributing structures
may be written.
..S S S S.... ..
Copper-meditated nucleophilic substitutions of halo thiophenes are also
of great synthetic utility. Examples of some transformation follow
S I
CuC CH
Pyridin / S H
S IH3C
Pyridin /
CuCN
8hrsS CNH3C
S Brquinolinde
S(Bu)
S SBu
Cu
Condensed Five-Membered
Heterocycles
Fusing benzene ring with 2,3-positions of furan, pyrrole and
thiophene leading to benzo[b]furan, indole and
benzo[b]thiophene, respectively.
O NH
S
benzo[b]furan indole benzo[b]thiophene
The molecular orbital description of benzofused heterocycles with one
heteroatom is very similar to that furan, pyrrole and thiophene, the only added
feature being distribution of - electrons. The reactivity of these fused
heterocycles is lower than that of the parent heterocycle but still higher than that
of benzene.
Position 3- is preferred position for electrophilic attack in indole, since it results in
two more stable resonance structures in the aromatic sixtet of the benzene ring
is preserved, which attack at position 2-yield one structure only in which the
aromatic sixtet is preserved.
NH
+ E
NH
E
H
NH
EH
NH
EH
Attack at position 2-
Attack at position 3-
NH
NH
N NPh
NH
SO3H
NH
NO2
NH
Br
NH
I
NH
CHO
N NHCH2NRR'
CH2NRR'
PhN2Cl
SO3 / pyridin
PhCONO3
N OOBr
H2O / KI3
POCl3 / DMF
Mannich
Electrophilic substitution in benzo[b]furan occurs
mainly at C-2.
O
O
O
O
CH3CONO3
POCl3 / DMF CHO
NO2
Ac2OCOCH3