Chapter 21 Electrophilic Aromatic Substitution (Material for at least 2 classes.
)
Reminder - Alkenes undergo addition reactions:
Benzene does not undergo addition reactions:
However, in the presence of a Lewis acid (FeBr3), benzene undergoes another reaction:
Br
+ Br2
FeBr3
+ HBr
Ho = -10.8 kcal/mol
Substitution rather than
addition occurs, and the aromatic system remains intact. This is an example of
electrophilic aromatic substitution. Electrophilic aromatic substitution is the most
important type of reaction of the aromatic ring.
The rate of a reaction is dictated by the E between the reactant(s) and the highest
energy transition state. It is common to view the relative energy or stability of the
intermediate as an approximation of the transition state energy.
There are many known electrophilic aromatic substitution reactions. Shown here are
just a few of the more common ones.
1
Chlorination Like bromination, electrophilic aromatic chlorination requires a Lewis acid
catalyst.
Cl
+ Cl2
AlCl3
+ HCl
Nitration see mechanism p. 476.
NO 2
H2SO4
+ HNO3
+ H2O
50o C
Sulfonation see mechanism p. 476.
SO3H
H2SO4
+ SO3
Friedel-Crafts reactions: Friedel-Crafts Acylation is
the reaction of an aromatic compound with an acid halide (acyl halide) in the presence
of a Lewis acid catalyst.
O
+
O
R
Lewis acid
+ HX
Mechanism p. 477
Friedel-Crafts Alkylation
+
Lewis acid
R
+ HX
Mechanism p. 477.
There are several limitations of Friedel Crafts alkylation reactions.
1. Alkylation (and acylation) do not occur readily with aromatic rings having
substituents that decrease the reactivity (deactivating groups).
2. Carbocation rearrangements may occur. Example: you want to make propyl
benzene.
CH 3
AlCl3
Cl
CH 3
isopropyl benzene
propyl benzene
Problem: carbocation rearrangement occurs
AlCl3
Cl
-H+
H
+
CH 3
H
CH 3
CH 3
H
+
H
3. Multiple substitution reactions may occur.
CH 3
R-Cl
R-Cl
R-Cl
FeCl3
FeCl3
FeCl3
An alternative approach do Friedel-Crafts Acylation followed by reduction.
O
O
Zn(Hg)
AlCl3
HCl
Cl
less reactive
than benzene
No rearrangement occurs and the reaction stops at monosubstitution. We will come to
the explanation for the latter soon. The reduction reaction is called the Clemmensen
reduction (p. 494 and p. 540).
Positional orientation in Electrophilic Aromatic Substitution on Substituted Benzenes
Br
Br
Br
Br2
Br
Br
FeBr3
+
Br
Br
ortho
para
meta
3
statistical distribution
observed distribution
Other examples
OCH 3
20%
87%
40%
13%
OCH 3
OCH 3
Br2
40%
<1%
OCH 3
Br
+
FeBr3
+
Br
Br
4%
96%
<<1%
NO 2
NO 2
Br2
Ag2SO4
aq. H2SO4
Br
100% (essentially no ortho or para
products)
Substituent groups can be divided into two main categories.
1. ortho, para directors
2. meta directors
ortho and para are produced together though the ortho/para ratio may vary with different
groups and different reaction conditions.
The ortho, para directing groups are:
O
O
R(alkyl), NH2, NR2, NH
R , OH, OR, O
R , F, Cl, Br, I
All except alkyl groups have at least one unshared electron pair on the atom attached to
the ring.
The meta directing groups are:
O
N
+
O
O-
O
OH
O
OH
O
OR
Meta directors are deactivating they make the benzene ring less reactive to
electrophilic aromatic substitution.
Most ortho, para directors are activating. The exceptions are the halogens, which are
deactivating.
4
First look at substitution of toluene at the ortho, meta, and para positions and the cation
intermediate formed in each.
CH 3
CH 3
Y+
CH 3
H
CH 3
H
ortho
CH 3
H
-H
+
3o carbocation
CH 3
meta
CH 3
CH 3
-H+
+
Y
Y+
+
no 3o carbocation
CH 3
CH 3
para
CH 3
CH 3
CH 3
-H+
+
+
H
H Y
H Y
3 carbocation
Ortho and para substitution are favored because one resonance structure of the
intermediate is a 3 carbocation. In meta substitution, all of the resonance structures
are 2 carbocations.
Look at the energetics of the first step of the reaction. The first step (formation of the
intermediate) is rate determining so we dont need to look at the second step.
The activation energy for substitution at the meta position of toluene is very close to that
for benzene, but the activation energy for substitution at the ortho and para positions is
much lower.
Now look at electrophilic aromatic substitution of nitrobenzene.
-
N+
N+
Y+
N
+
+
O
H
Y
ortho
-H+
+
cations on adjacent atoms
meta
N+
N+
N+
N+
-H+
para
N+
Y+
Y+
+
H
H
H
all three resonance structures have chages separated by at least one atom
-
N+
N+
N+
N+
-H+
+
+
H Y
H Y
cations on adjacent atoms
H Y
For ortho and para substitution, one of the resonance structures is of very high energy,
having positive charge on adjacent atoms (positive charge is on the carbon atom
bearing the strongly electron withdrawing nitro group). The intermediate formed in meta
substitution is also destabilized by the nitro group but less so than the intermediates
formed in ortho or para substitution. Look at the free energy profile:
Nitrobenzene is less
reactive than benzene in substitution at the meta position but is even less reactive in
substitution at the ortho and para positions.
The same principles apply to other substituents. For an alkoxy group:
O-CH 3
Y+
ortho
O-CH 3
H
+
O-CH 3
H
O-CH 3
H
+
+
O-CH 3
H
Y
+
oxonium ion
Y+
O-CH 3
meta
O-CH 3
+
+
Y
para
O-CH 3
O-CH 3
Y+
O-CH 3
Y
+
+
O-CH 3
O-CH 3
+
+
+
H Y
H Y
oxonium ion
H Y
The intermediates for ortho and para substitution are stabilized by the oxonium ion
resonance structure, which more than compensates for the destabilizing inductive effect
of oxygen. (Structures having more bonds and/or in which all atoms have an octet of
electrons are generally more stable.) Other substituents having unshared electron pairs
on atoms attached directly to the aromatic ring form similar resonance structures.
7
The intermediate for meta substitution does not have an oxonium ion form and is only
destabilized by the inductive effect of oxygen.
The effect of substituents is felt most at the ortho and para positions.
Thus activating groups activate the ortho and para positions the most.
Deactivating groups deactivate the ortho and para positions the most so that meta
substitution is observed.
How do we explain the halogens, which are deactivating ortho, para directing groups?
Cl
Y+
ortho
+
Cl
Cl
Cl
Cl
+
chloronium ion
Y+
Cl
meta
Cl
Cl
+
Y
Y+
para
+
Cl
Cl
Cl
Cl
+
+
+
H Y
H Y
chloronium ion
As with the O-CH3 group, the intermediates in ortho and para substitution are stabilized
by resonance structures in which the attached atom bears the positive charge.
However, the inductive effect of the halogen is greater than this resonance effect.
In meta substitution, only the inductive effect is important whereas for ortho and para
substitution, the inductive effect is partially compensated by the resonance effect.
Look at the energy profile:
The activation energy for electrophilic aromatic substitution of halobenzenes is higher
than that for benzene due to the inductive effect of the halogen. The activation energy
for substitution at the ortho and para positions is brought back down to near the level of
benzene due to the resonance effect.
Electrophilic aromatic substitution of disubstituted benzenes.
CH 3
>99%
NO 2
Both substituents favor reaction at the position ortho to the methyl group and meta to
the nitro group.
O
C OH
Br
4% o,o
Br
0% m,m
Br
80%
96% o,p
20%
Substitution ortho
or para to bromine
Substitution meta to the carboxylic acid
is favored. Very little of the 1,2,3-substituted and ortho or para to bromine is favored.
product is observed, due to steric effects.
In all of the above cases, the substituents are reinforcing.
What about cases when the orientational preferences are conflicting. Usually activating
groups have the dominant effect.
9
Synthetic applications of electrophilic aromatic substitution. The order of reactions is
often important.
NO 2
+ Cl2
NO 2
AlCl3
Cl
Cl
HNO3
Cl
Cl
+
H2SO4
NO 2
NO 2
If you want the meta product, introduce chlorine last while if the ortho or para product is
desired, introduce the nitro group last.
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