Electrophilic aromatic
substitution
© E.V. Blackburn, 2011
Substitution?
The characteristic reactions of benzene involve
substitution in which the resonance stabilized ring
system is maintained:
HNO 3/H2SO4
NO 2
© E.V. Blackburn, 2011
Reactivity
- an electron source, benzene reacts with electron
deficient reagents - electrophilic reagents.
© E.V. Blackburn, 2011
Electrophilic aromatic
substitution
1. Nitration
ArH + HNO3/H2SO4
ArNO2 + H2O
2. Sulfonation
ArH + H2SO4/SO3
ArSO3H + H2O
3. Halogenation
ArH + X2/FeX3
ArX + HX
© E.V. Blackburn, 2011
Friedel - Crafts reactions
4. Friedel - Crafts alkylation
ArH + RCl/AlCl3
ArR + HCl
5. Friedel - Crafts acylation
ArH + RCOCl/AlCl3
ArCOR + HCl
Ar
R
O
© E.V. Blackburn, 2011
Substituent effects
CH3
CH3
HNO 3
NO 2
+
H2SO4
25C
CH3
CH3
+
NO 2
NO 2
34%
63%
3%
Toluene is more reactive than benzene.....
© E.V. Blackburn, 2011
Reactivity
How is “reactivity” determined in the lab?
• Compare the time required for reactions to occur
under identical conditions.
• Compare the severity of reaction conditions.
• Make a quantitative comparison under identical
reaction conditions.
© E.V. Blackburn, 2011
Substituent effects
In some way, the methyl group makes the ring more
reactive than that of the unsubstituted benzene
molecule.
It also directs the attacking reagent to the ortho and
para positions on the ring.
© E.V. Blackburn, 2011
Substituent effects
NO 2
NO 2
NO 2
NO 2
NO 2
HNO 3
+
+
NO 2
H2SO4
25C
NO 2
2%
7%
91%
Nitrobenzene undergoes substitution at a slower
rate than does benzene. It yields mainly the meta
isomer.
© E.V. Blackburn, 2011
Substituent effects
A group which makes the ring more reactive than that
of benzene is called an activating group.
A group which makes the ring less reactive than
benzene is called a deactivating group.
A group which leads to the predominant formation of
ortho and para isomers is called an “ortho - para
directing group.”
A group which leads to the predominant formation of
the meta isomer is called a “meta directing group.”
© E.V. Blackburn, 2011
Activating, o,p directors
All activating groups are o,p directors.
strongly activating
-OH
-NH2 -NHR -NR2
A
moderately activating
-OR
-NHCOR
weakly activating
-aryl
-alkyl
© E.V. Blackburn, 2011
Deactivating, m directors
All m directors are deactivating.
-NO2
-SO3H
-CO2H
-CO2R
-CONH2
-CHO
-COR
-CN
+
-NH3

 O or N
+
-NR3
A
© E.V. Blackburn, 2011
Deactivating, o, p directors
-F, -Cl, -Br, -I
© E.V. Blackburn, 2011
Orientation in disubstituted
benzenes
CH3
H2SO4
CH3
NO 2
HNO 3
NO 2
NO 2
Here the two directing effects are additive.
© E.V. Blackburn, 2011
Orientation in disubstituted
benzenes
When two substituants exert opposing directional
effects, it is not always easy to predict the products
which will form. However, certain generalizations can
be made....
© E.V. Blackburn, 2011
Orientation in disubstituted
benzenes
• Strongly activating groups exercise a far greater
influence than weakly activating and all deactivating
groups.
OH
OH
HNO 3/H2SO4
CH3
NO 2
CH3
© E.V. Blackburn, 2011
Orientation in disubstituted
benzenes
• If there is not a great difference between the
directive power of the two groups, a mixture results:
CH3
HNO 3
CH3
CH3
NO 2
+
NO 2
H2SO4
Cl
Cl
58%
Cl
42%
© E.V. Blackburn, 2011
Orientation in disubstituted
benzenes
• Usually no substitution occurs between two meta
substituents due to steric hindrance:
37%
Cl
1%
Br
62%
......nitration
© E.V. Blackburn, 2011
Synthesis of mbromonitrobenzene
In order to plan a synthesis, we must consider the order
in which the substituents are introduced.......
NO 2
NO 2
Br2/FeBr3
HNO 3
H2SO4
Br
If, however, we brominate and then nitrate, the o and
p isomers will be formed.
© E.V. Blackburn, 2011
Orientation and synthesis
If a synthesis involves the conversion of a substituants
into another, we must decide exactly when to do the
conversion.
Let’s look at converting a methyl group into a
carboxylic acid:
Now let’s see how we can make the three nitrobenzoic
acids:
© E.V. Blackburn, 2011
The nitrobenzoic acids
KMnO 4
CO2H
HNO 3
CO2H
H2SO4
CH3
NO 2
m-nitrobenzoic acid
HNO 3
CH3
CH3
NO 2
+
H2SO4
NO 2
bp 225oC
bp 238oC
© E.V. Blackburn, 2011
The nitrobenzoic acids
CH3
CH3
NO 2
+
K2Cr2O7
CO2H
NO 2
o-nitrobenzoic acid
NO 2
K2Cr2O7
CO2H
NO 2
p-nitrobenzoic acid
© E.V. Blackburn, 2011
Nitration
H3O+ + 2HSO4- + NO2+
nitronium
+
ion - a Lewis
H
acid
NO
HONO2 + 2H2SO4
+
NO2
2
-
+
HSO4
H
NO2
NO 2
H2SO4 +
© E.V. Blackburn, 2011
The structure of the
intermediate carbocation
+
H
NO 2
H
NO 2
+
O2N
+
H
NO2
H
+
The positive charge is not localized on any one carbon atom.
It is delocalized over the ring but is particularly strong on the
carbons ortho and para to the nitro bearing carbon.
© E.V. Blackburn, 2011
Sulfonation
H3O+ + HSO 4- + SO3
2H2SO4
O
S O
O
+
SO3
H
HSO4
+
SO3H
-
SO3H2SO4 +
-
© E.V. Blackburn, 2011
Halogenation
Br Br
FeBr3
+ Br Br FeBr3
+
Br
H
Br FeBr3
+
Br Br FeBr3
+ Br Br FeBr3
+
Br
H + FeBr4
Br
+ HBr + FeBr 3
© E.V. Blackburn, 2011
Friedel - Crafts alkylation
R X
AlX 3
+
R
+
R
H
+
R + AlX 4
+
R
H
R
X AlX 3
+ AlX 3
© E.V. Blackburn, 2011
An electrophilic carbocation?
(CH3)3COH + H +
+
(CH3)3COH 2
(CH3)3COH/H +
+
(CH3)3COH 2
H2O + (CH3)3C+
C(CH3)3
© E.V. Blackburn, 2011
An electrophilic carbocation?
(CH3)2C=CH2 + H+
(CH3)2C=CH 2/H+
(CH3)3C+
C(CH3)3
© E.V. Blackburn, 2011
An electrophilic carbocation?
CH2CH2CH3
CH3CH2CH2Cl
CH(CH 3)2
+
AlCl 3
~33%
~67%
© E.V. Blackburn, 2011
An electrophilic carbocation?
When RX is primary, a simple carbocation does
not form. The electrophile is a complex:
  H3C Cl AlCl 3
© E.V. Blackburn, 2011
Limitations
• Aromatic rings less reactive than the halobenzenes
do not undergo Friedel - Crafts reactions.
• A polysubstitution is possible - the reaction
introduces an activating group!
• Aromatic compounds bearing -NH2, -NHR or -NR2
do not undergo Friedel - Crafts substitution. Why?
© E.V. Blackburn, 2011
Friedel - Crafts acylation - the
reaction
Cl
O
+
AlCl 3
+ HCl
O
© E.V. Blackburn, 2011
Friedel - Crafts acylation
O
R
X
+
RC O
+
acylium ion
O
+
H
R
O
O
H
+
RC O + AlX 4
+
RC O
+ AlX 3
R
X AlX 3
R
+ HX + AlX 3
© E.V. Blackburn, 2011
Limitations
Cl
NO 2
+
O
AlCl 3
?
© E.V. Blackburn, 2011
The mechanism
E
+ E+
E
+
slow, rate
determining step
E
H
+
H
+ Nu:
fast
Evidence - there is no significant deuterium isotope effect.
© E.V. Blackburn, 2011
Isotope effects
A difference in rate due to a difference in the isotope
present in the reaction system is called an isotope
effect.
© E.V. Blackburn, 2011
Isotope effects
If an atom is less strongly bonded in the transition state
than in the starting material, the reaction involving the
heavier isotope will proceed more slowly.
H
C H + Z
k
C H Z
C + HZ
The isotopes of hydrogen have the greatest mass
differences. Deuterium has twice and tritium three times
the mass of protium. Therefore deuterium and tritium
isotope effects are the largest and easiest to determine.
© E.V. Blackburn, 2011
Primary isotope effects
These effects are due to breaking the bond to the
isotope.
C H + Z
C D + Z
kH
kD
C H Z
C + HZ
C D Z
C + DZ
kH
D = 5-8
k
Thus the reaction with protium is 5 to 8 times faster than
the reaction with deuterium.
© E.V. Blackburn, 2011
Evidence for the E2
mechanism - a large isotope
effect
kH
CH3CHCH 3
NaOEt
Br
kD
CD3CHCD 3
NaOEt
Br
CH3CH=CH 2
CD3CH=CD 2
kH/kD = 7
© E.V. Blackburn, 2011
The mechanism
E
+ E+
E
+
slow, rate
determining step
E
H
+
H
+ Nu:
fast
Evidence - there is no significant deuterium isotope effect.
© E.V. Blackburn, 2011
The reactivity of aromatic
rings
+
The transition state for the
rate determining step:
E
H
+
Factors which stabilize carbocations by dispersal of
the positive charge will stabilize the transition state
which resembles a carbocation; it is a nascent
carbocation.
© E.V. Blackburn, 2011
Carbocation stability
E
H
+
E
H
+
CH3
electron donation
stabilizes the
carbocation
E
H
+
NO 2
electron withdrawal
destabilizes the
carbocation
© E.V. Blackburn, 2011
Orientation
An activating group activates all positions on the
ring but directs the attacking reagent to the ortho
and para positions because it makes these
positions more reactive than the meta position.
A deactivating group deactivates all positions on
the ring but deactivates the ortho and para
positions more than the meta position.
Why? Examine the transition state for the rate
determining step for ortho, meta and para attack.
© E.V. Blackburn, 2011
CH3 - an o/p director
ortho
attack
E
H
CH3
+
E
H
CH3
E
+
H
E
+
H
CH3
+
3°
E
meta
attack
E
H
+
CH3
CH3
E
para
attack
H
+
H
+
E
H
CH3
E
+
H
+
CH 3
CH3
3°
CH3
© E.V. Blackburn, 2011
NO2 - a m director
E
ortho
H
+
E
meta
NO 2
E
NO 2
E
+
H
E
+
H
NO 2
+
H
+
E
H
+
para
H
+
NO 2
E
H
E
NO 2
H
NO 2
E
+
H
+
NO 2
NO 2
NO 2
© E.V. Blackburn, 2011
NO2 - a m director
E
H
+
para
E
H
E
+
H
+
NO 2
NO 2
E
H
+
+
N
O O
-
NO 2
E
H
+

C
H3C O 
© E.V. Blackburn, 2011
NH2 - an o/p director??
E
H +
NH2
E
H
NH 2
+
E
E
H
E
H
+
H
+
NH 2
E
+
H
E
+
H
NH 2
+
E
H
+
NH 2
E
H
E
NH 2
H
NH 2
E
+
H
+
NH 2
+
NH 2
: NH 2
NH 2
© E.V. Blackburn, 2011
Halogen - a deactivating
group
E
H
+
Deactivation results from electron withdrawal:
E
H
+
Cl
© E.V. Blackburn, 2011
Halogen - an o/p directing
group
o/p directors are electron donating. How can a halogen
substituent donate electrons?
© E.V. Blackburn, 2011
Halogen - an o/p directing
group
E
H
+
E
Cl
E
H
Cl
E
+
H
E
+
H
Cl
E
H +
Cl
E
H
+
H
+
E
+
Cl
E
H
+
H
E
Cl
H
Cl
E
+
H
+
Cl
Cl
Cl
+ Cl
© E.V. Blackburn, 2011
© E.V. Blackburn, 2011