Chapter 2 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 π rule.
Nonaromatic compound: All atoms are not sp2 hybridized.
Aromatic compounds
N
cyclic, conjugate Sp2 2 pi electrons (4n+2 rule) planar
N H
cyclic, conjugate Sp2 6 pi electrons (4n+2 rule) planar
N N
cyclic, conjugate Sp2 10 pi electrons (4n+2 rule) planar
N H
N H
cyclic, conjugate Sp2 14 pi electrons (4n+2 rule) planar
Antiaromatic compounds H N
cyclic, conjugate Sp2 4 pi electrons (4n rule) planar
cyclic, conjugate Sp2 8 pi electrons (4n rule) planar
Nonaromatic compounds
Have separate sp3 atoms (i.e not all atoms are sp2)
The resonance energy of benzene A compound with delocalized electrons is more stable than it would be if all of its electrons were localized. The extra stability of the compound gains from having delocalized electrons is called delocalization energy or resonance energy .
To understand the concept of resonance energy, let’s take a look at the resonance energy of benzene. In other words, let’s see how much more stable benzene (with three pairs of delocalized electrons) is than the unknown, unreal, hypothetical compound “cyclohexatriene” (with three pairs of localized electrons).
+ H2
∆Ho = - 28.6kcal/mol .(experimentally)
cyclohexene
+ 2H2
∆Ho = -55.4 kcal/mol. (experimentally)
1,3-cyclohexadiene
+ 3H2
∆Ho = -85.8 kcal/mol. (theoritically)
“cyclohexatriene” hypothetica
+ 3H2 benzene
∆Ho = -49.8 kcal/mol. (experimentally)
The experimental ∆Ho for the hydrogenation of benzene is 36 kcal/mo less than that calculated for “cyclohexatriene�. We define the stabilization energy or resonance energy, of a substance as the difference between the actual energy of the real molecule (the resonance hybrid) and the calculated energy of the most stable contributing structure. Consequently, as we will see, benzene and other aromatic compounds usually react in such a way as to preserve their aromatic structure and therefore retain their resonance energy.
Bond length in heterocycles It is a general property of aromatic compounds that the lengths of the bonds in the rings are intermediate between the values in single and double bonds. In benzene the bond lengths are equal (1.395Å) whereas in conjugated acyclic polyene the bond lengths alternate. C―C : 1.48
C═C : 1.34
C―N : 1.45
C═N : 1.27
C―O : 1.36
C═O : 1.22
C―S : 1.75
C═S : 1.64
N―N : 1.41
N═N : 1.23
1.38 N 1.37 H
H2C
C H
1.34Αο C H
CH2
1.361 O 1.362
1.37 S
1.39Αο
1.39
1.42
1.43
1.41
1.48Αο
1.71
1.39 N 1.34
The π-excessive heterocyclic compounds They are Planar, fully conjugated, monocyclic systems with 6π π electrons [i.e. follow (4n + 2)π π electrons ,)n is an integer 0, 1, 2, etc.)] In benzene each carbon corner has one unit of pi-electron, but this system (π π-excessive) has in each corner more than one π-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 R.E.
16
N H 21
S 29
In terms of valence bond theory these compounds are resonance hybrids. However, resonance structures have charge separation.
X
X
X X = O, N, S
X
X
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. KekulÊ forms
N
N
N
N
N
As a result the reactivity pattern toward electrophiles similar to that of πdeficient benzene derivatives e.g. nitrobenzene. Moreover, having p-deficient carbon these molecules are reactive towards nucleophiles.
Reactivity of Five membered piExcessive Heterocyclic ring Reactivity towards electrophilic substitution Pyrrole, furan and thiophene are all much more reactive than benzene toward electrophilic substitution.
benzene
S
O
thiophene
furan
N H pyrrole
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.
E
E
attack at C-2 X
X
H
E X
E
X
H
H X
E
E H
X
-
H
E
X = NH, O, S attack at C-3
E
- H X
X
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
substitution takes place at 3-position.
occupied,
electrophilic
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.
Resonance energy
N
S
O
H
21 Kcal/mol
16 Kcal/mol
25 Kcal/mol
Reactivity sequence
Energy needed to go from the more aromatic pyrrole to its reactive intermediate is less than energy needed for a similar step with furan
E N
N
H
H
E
N H
E
O
E
Less energy demand
E O
O
E
P. E
O
+E
Reactive
O
+E N H
∆G*
N H
E
E
1- It was found that pyrrole reacts readily with some weak electrophiles, while thiophene and furan did not react Ar N
N Cl
N
Ar
N
N H
R N H
Mannish reaction ArCHO / R2NH
N N H Ar
Ar N
N Cl
O
No reaction
Mannish reaction S
R
2- Halogenation. Just as is true for aniline, the pyrrole ring is reactive toward bromine or chlorine, giving polysubstituted products Br
Br
Br2 N H
Br
Br
N H
3- On the other hand, Due to the low aromaticity of furan, it reacts differently towards bromine Br2 O
o
O
CS2, -5 C
Br
Br
O Br
heat O
Br
- HBr
Br
O
Br
4. Due to the sensitivity to acids nitration is conducted in aprotic media.
5- Only thiophene (least acid reactive can be nitrated by mixed acid nitration.
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.
HNO 3 O
NO 2
O
Ac2O, -5 oC
NO2
O
AcO
heat O
NO 2
AcO - AcOH
O
NO 2
7. Acylation of π-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 CAc2O N H
AcONa
N COCH3
Ac2O N
H 2O
MgBr
CH3 N H
O
Furan and thiophene undergo Friedel –Craft reaction while pyrrole did not?
Ac2O O
AcONa
CH 3 O O
Ac2O S
ZnCl2
CH3 S O
Reactions of Furan Cl2 in CH2Cl2 O
Cl
O
Br
Br2 in Dioxan -5oC
HNO3 fuming o
O
Ac2O / -5 C
AcO
O
SO3 / pyridine O
SO3H
O
COCH3
(CH3CO)2O BF3 / 0oC
NO2
O
NO2
Reactions of Thiophene I2 I
S O
Br N O Br
S
NO 2 +
HNO 3 / H 2SO 4 S
S
NO 2
S 6
:
H 2SO 4 (95%) room temp
S
SO 3H
S
COCH 3
Ac2O / SnCl4 or ZnCl2
1
Reactions of Pyrrole X X2
X
X X
N H
NO2 CH3 CONO3 - 10 oC
+ N H
NO2 50 %
:
N H 13%
SO3 / pyridin SO3H
N H
N H + PhN2Cl
N H
N=NPh
Ac2O N COCH3 CH2O / R2NH N H
CH2NR2
Acidic character 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.
KOH + N H
N K
H2O
The acidic character of pyrrole is due to Pyrrole is a resonance hybrid of various structures carrying a positive charge on nitrogen. The greater stability of pyrrole anion compared to pyrrole. .. N
N H
+
H+
The higher stability of the anion is due to resonance.
N
N
N
N
The acidic character is also reflected in the formation of pyrrolyl magnesium halide when reacted with alkylmagnesium halide.
RX N
N
K
R
N H
C O2 N N + MgBr
COOH
H R C O Cl N H
COR
R
The action of acids pyrrole, thiophene and furan
H
HCl N H
trimerization
4 5
3
N H
S
2
N H
S
3
4
1
5
S
H2O O H
H
N H
2
trimerization
H O
H
1
H3PO4 S
H
OHC
CHO
The mechanism of trimerization of pyrrole in acid medium
H
H H
HCl
N H
H
N H
N H
N H
N H
HCl H H H N H
H N H
N H
N H
N H
Substituted Effects on Electrophilic Substitution 1- Electron-withdrawing substituents (W) at the position “α” to the heteroatom generally cause substitution at the 4- and / or 5-position.
E+
E+
X
W
2- Electron-donating substituents (D) at the position “α” to the heteroatom tend to cause substitution at both the remaining “α” position (C-5) and at the 3-position.
+
E
+
E
X
D
3- Electron-withdrawing substituents (W) at the position “β” to the heteroatom facilitate substitution at position 5.
W E
+
X
4- Electron-donating substituents (D) at the position “β β” to the heteroatom generally cause substitution to take place at the 2-position.
D
X +
E
Nucleophilic Substitutions in Pyrrole, Furan and Thiophene We have seen that the reactivity of pyrrole, furan and thiophene towards electrophilic substitution is in the following order
N H
O
S
The reactivity of these rings towards nucleophilic substitution is in the opposite order
N H
O
S
Pyrroles:
the pyrrole ring is the least reactive and both 2-
halo-
3-halopyrroles
and
behave
like
aryl
halides
in
nucleophilic displacement. Thus, 2-chloropyrrole does not react with potassium tert-butoxide or with lithium aluminum hydride
KOC(CH3)3
Cl
No reaction
N H LiAlH4
No reaction
Furans
are more reactive towards nucleophilic displacement than pyrrole. 2-bromo- and 2-chloro react with piperidine at 200oC as follows: : Nu
- Br Nu
X
Br
X
X
Br
X = O, S
HN O
Br
200oC
O
N
Nu
The presence of electron-withdrawing groups on the furan ring facilitates nucleophilic displacement. Thus, 2-bromo-5nitrofuran and methyl 2-bromo-5-carboxylate react readily with nucleophiles
HN O2N
O
Br
o
25 C
O2N
O
N
• 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-bromo5-nitrothiophene.
O
Nu
N O
S
Br
III
Nu
Nu O2N
S
Br
O2 N
O S
Nu
N O
Br
I
S
Br
II
O N O
Nu S
Br
IV
It is suggested that the sulfur atom causes additional stabilization by involvement of its d-orbitals "Structure III"
It must be noted that the lone pair of the sulphur atom also enters into resonance with the π 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.
Copper-meditated nucleophilic substitutions of halo thiophenes are also of great synthetic utility. Examples of some transformation follow
CuC CH I
S
CuCN H3C
S
I
Pyridin /
H
S
Pyridin /
H3C
S
CN
8hrs
Cu S(Bu) S
Br
quinolinde
S
SBu
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 benzo[b]furan
N H indole
S 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 π- 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.
+ N H
E
Attack at position 2-
E N H H Attack at position 3-
H
N H
E
H
N H
E
N N Ph PhN2Cl N H
SO3H
SO3 / pyridin N H NO2 PhCONO3
O
N H
Br N O
N H
Br
N H
I H2O / KI3 N H
CHO
POCl3 / DMF N H CH2NRR' Mannich N CH2NRR'
N H
Vilsmeier–Haack Formylation with N,NDimethylformamide. The mechanism of the reaction involves first the phosphorylation of the carbonyl oxygen of the formamide with POCl3 to form a dichlorophosphate. Chloride ion then displaces the phosphate group, which forms the electrophilic species that attacks the ring. Hydrolysis of the imino group restores the carbonyl group. POCl3
Cl Me2N
Me2NCH=O
CHOPOCl2
Me2N Me N
Me2N
Me
CHCl
N H
N H CHO
H2 O N H
CHCl
Electrophilic substitution in benzo[b]furan occurs mainly at C-2.
Both C-2 and C-3 of benzo[b]thiophene are involved as the intermediates are of comparable stability.