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762 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES
16.19 Show two different Friedel–Crafts acylation reactions that can be used to prepare the follow-
ing compound.
16.20 The following compound reacts with AlCl
3
followed by water to give a ketone A with the for-
mula C
10
H
10
O. Give the structure of A and a curved-arrow mechanism for its formation.
ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS
OF SUBSTITUTED BENZENES
A. Directing Effects of Substituents
When a monosubstituted benzene undergoes an electrophilic aromatic substitution reaction,
three possible disubstitution products might be obtained. For example, nitration of bromoben-
zene could in principle give ortho - , meta - , or para -bromonitrobenzene. If substitution were
totally random, an ortho:meta:para product ratio of 2 : 2 :1 would be expected. (Why?) It is
found experimentally that this substitution is not random, but is regioselective.
Other electrophilic substitution reactions of bromobenzene also give mostly ortho and para
isomers. If a substituted benzene undergoes further substitution mostly at the ortho and para
positions, the original substituent is called an ortho, para-directing group. Thus, bromine is
an ortho, para-directing group, because all electrophilic substitution reactions of bromoben-
zene occur at the ortho and para positions.
In contrast, some substituted benzenes react in electrophilic aromatic substitution to give
mostly the meta disubstitution product. For example, the bromination of nitrobenzene gives only
the meta isomer.
Other electrophilic substitution reactions of nitrobenzene also give mostly the meta isomers.
If a substituted benzene undergoes further substitution mainly at the meta position, the origi-
(16.28)
NO
2
NO
2
M
i
i
Br
nitrobenzene m -bromonitrobenzene
(only product observed)
Br 2
FeBr 3
heat
(16.27) i
Br
NO
2
NO
2
M
NO
2
M
i
Br
i
Br
i
Br
o -bromonitrobenzene
(36%)
p -bromonitrobenzene
(62%)
m -bromonitrobenzene
(2%)
HNO 3
acetic acid
bromobenzene
C
O
L L L Cl
S
H L
3
C CH
2
CH
2
L L L
S
O
C
CH
3
CH
3
CH
3
c c
)
)
16.5 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF SUBSTITUTED BENZENES 763
nal substituent group is called a meta-directing group. Thus, the nitro group is a meta-
directing group because all electrophilic substitution reactions of nitrobenzene occur at the
meta position.
A substituent group is either an ortho, para-directing group or a meta-directing group in
all electrophilic aromatic substitution reactions; that is, no substituent is ortho, para directing
in one reaction and meta directing in another. A summary of the directing effects of common
substituent groups is given in the third column of Table 16.2.
16.21 Using the information in Table 16.2, predict the product(s) of
(a) Friedel–Crafts acylation of anisole (methoxybenzene) with acetyl chloride (structure in
Eq. 16.23) in the presence of one equivalent of AlCl
3
followed by H
2
O.
(b) Friedel–Crafts alkylation of a large excess of ethylbenzene with chloromethane in the
presence of AlCl
3
.
PROBLEM
Summary of Directing and Activating or
Deactivating Effects of Some Common Functional Groups
(Groups are listed in decreasing order of activation.)
Activating or
Substituent group Name of group Directing effect deactivating
amino
hydroxy
alkoxy
acylamino
LR alkyl
acyloxy
phenyl
,
halogens
acyl
LSO
3
H sulfonic acid
LCN cyano
LNO
2
nitro
C
$
R
O
L
carboxy, carboxamido,
carboalkoxy
C ,
$
OH
O
L C ,
$
NH
2
O
L C
$
OR
O
L
F 3
1
1
L I 3
1
1
L Br 3
1
1
L Cl 3
1
1
L
, , ,
L
O C
$
R
O
L 2 L
2
NH C
$
R
O
L L 2
OR
L 2
2
L OH 2
2
NH
2
L , 2
NR
2
L 2
TABLE 16.
meta
directors
deactivating
substituents
ortho, para
directors
activating
substituents
16.5 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF SUBSTITUTED BENZENES 765
bons of the ring. When meta substitution occurs, the positive charge is not shared by the carbon
adjacent to the oxygen.
We now use the resonance structures in Eqs. 16.29 and 16.30 (as well as those you drew in
Problem 16.22) to assess relative rates. The logic to be used follows the general outline given
in Study Problem 15.3, page 715. A comparison of Eq. 16.29 and the structures you drew for
Problem 16.22 with Eq. 16.30 shows that the reaction of an electrophile at either the ortho or
para positions of anisole gives a carbocation with more resonance structures—that is, a more
stable carbocation. The rate-limiting step in many electrophilic aromatic substitution reactions
is formation of the carbocation intermediate. Hammond’s postulate (Sec. 4.8D) suggests that
the more stable carbocation should be formed more rapidly. Hence, the products derived from
the more rapidly formed carbocation—the more stable carbocation—are the ones observed.
Because the reaction of the electrophile at an ortho or para position of anisole gives a more sta-
ble carbocation than the reaction at a meta position, the products of ortho, para substitution are
formed more rapidly, and are thus the products observed (see Fig. 16.5). This is why the
LOCH
3
group is an ortho, para-directing group.
To summarize: Substituents containing atoms with unshared electron pairs adjacent to the
benzene ring are ortho, para directors in electrophilic aromatic substitution reactions because
their electron pairs can be involved in the resonance stabilization of the carbocation inter-
mediates.
Now imagine the reaction of an electrophile E
|
with an alkyl-substituted benzene such as
toluene. Alkyl groups such as a methyl group have no unshared electrons, but the explanation
reaction coordinates
CH
3
O 21
r
M
CH
3
O
+ E
|
D G 8
‡
(para
substitution)
(a)
`
more stable
carbocation
intermediate
CH
3
O 21
`
!!
r
M
CH
3
O
+ E
|
D G 8
‡
(meta
substitution)
(b)
M
CH
3
O 21
`
less stable
carbocation
intermediate
M
CH
3
O 21
`
H E
H E
!!
H
E
H
E
STANDARD FREE ENERGY
d +
d +
d +
d +
d +
faster reaction slower reaction
Figure 16.5 Basis of the directing effect of the methoxy group in the electrophilic aromatic substitution
reactions of anisole. Substitution of anisole by an electrophile E
|
occurs more rapidly at (a) the para position than
at (b) the meta position because a more stable carbocation intermediate is involved in para substitution. The
dashed lines within the structures symbolize the delocalization of electrons.
766 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES
for the directing effects of these groups is similar. Reaction of E
|
at a position that is ortho or
para to an alkyl group gives an ion that has one tertiary carbocation resonance structure (col-
ored structure in the following equation).
Reaction of the electrophile meta to the alkyl group also gives an ion with three resonance
structures, but all resonance forms are secondary carbocations.
Because reaction at the ortho or para position gives the more stable carbocation, alkyl groups
are ortho, para-directing groups.
Meta-Directing Groups The meta-directing groups in Table 16.2 are all polar groups
that do not have an unshared electron pair on an atom adjacent to the benzene ring. The di-
recting effect of these groups can be understood by considering as an example the reactions
of a general electrophile E
|
with nitrobenzene at the meta and para positions.
(16.34)
|
|
|
N
M
!!
para
H
E
i
M M
3 O 3
S
|
N
M M
3 O 3
S
|
|
N
M M
3 O 3
S
p q
H
E
M
M
H
E
M
M
H
E
M
M
|
|
N
M M
3 O 3
S
o
positive charges on
adjacent atoms
_
21 O
_
O
_
O
_
O
(16.33)
|
|
|
N
M
!!
meta
H
E
i
|
H
E
M
M
H
E
M
M
H
E
M M
M M
3 O 3
S
|
N
M M
3 O 3
S
|
N
M M
3 O 3
S
p q
| |
N
M M
3 O 3
S
d
_
O 21
_
O 21
_
O
_
O
(16.32)
|
|
CH
3
M
CH
3
M
CH
3
CH
3
M
!!
meta
H
H E
E
i s
|
|
M
H E
s
H E
e
(16.31)
|
|
CH
3
H
M
M
CH
3
M
!!
para
E
i s
|
CH
3
M
t
|
CH
3
M
p
tertiary carbocation
H
E
H
E
H
E
768 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES
found that the para substitution product is the major one in the reaction mixture. In some cases
this result can be explained by the spatial demands of the electrophile. For example,
Friedel–Crafts acylation of toluene gives essentially all para substitution product and almost
no ortho product. The electrophile cannot react at the ortho position without developing van
der Waals repulsions with the methyl group that is already on the ring. Consequently, reaction
occurs at the para position, where such repulsions cannot occur.
Typically, para substitution predominates over ortho substitution, but not always. For ex-
ample, nitration of toluene gives twice as much o -nitrotoluene as p -nitrotoluene. This result
occurs because the nitration of toluene at either the ortho or para position is so fast that it oc-
curs on every encounter of the reagents; that is, the energy barrier for the reaction is insignif-
icant. Hence, the product distribution corresponds simply to the relative probability of the re-
actions. Because the ratio of ortho and para positions is 2 :1, the product distribution is 2 :1.
In fact, the ready availability of o- nitrotoluene makes it is a good starting material for certain
other ortho-substituted benzene derivatives.
In summary, the reasons for the ortho, para ratio vary from case to case, and in some cases
these reasons are not well understood.
Whatever the reasons for the ortho, para ratio, if an electrophilic aromatic substitution re-
action yields a mixture of ortho and para isomers, a problem of isomer separation arises that
must be solved if the reaction is to be useful. Usually, syntheses that give mixtures of isomers
are avoided because, in many cases, isomers are difficult to separate. However, the ortho and
para isomers obtained in many electrophilic aromatic substitution reactions have sufficiently
different physical properties that they are readily separated (Sec. 16.2). For example, the boil-
ing points of o - and p -nitrotoluene, 220°C and 238°C, respectively, are sufficiently different
that these isomers can be separated by careful fractional distillation. Thus, either isomer can
be obtained relatively pure from the nitration of toluene. The melting points of o - and p -
chloronitrobenzene, 34°C and 84°C, respectively, are so different that the para isomer can be
selectively crystallized. As you learned in Sec. 16.2, the para isomer of an ortho , para pair typ-
ically has the higher melting point, often considerably higher. Most aromatic substitution re-
actions are so simple and inexpensive to run that when the separation of isomeric products is
not difficult, these reactions are useful for organic synthesis despite the product mixtures ob-
tained. Thus, you may assume in working problems involving electrophilic aromatic substitu-
tion on compounds containing ortho, para-directing groups that the para isomer can be iso-
lated in useful amounts. For the reasons pointed out in the previous paragraph, o- nitrotoluene
is a relatively rare example of a readily obtained ortho - substituted benzene derivative.
B. Activating and Deactivating Effects of Substituents
Different benzene derivatives have greatly different reactivities in electrophilic aromatic sub-
stitution reactions. If a substituted benzene derivative reacts more rapidly than benzene itself,
then the substituent group is said to be an activating group. The Friedel–Crafts acylation of
anisole (methoxybenzene), for example, is 300,000 times faster than the same reaction of ben-
zene under comparable conditions. Furthermore, anisole shows a similar enhanced reactivity
relative to benzene in all other electrophilic substitution reactions. Thus, the methoxy group is
an activating group.
On the other hand, if a substituted benzene derivative reacts more slowly than benzene it-
self, then the substituent is called a deactivating group. For example, the rate for the bromi-
nation of nitrobenzene is less than 10
_ 5
times the rate for the bromination of benzene; further-
more, nitrobenzene reacts much more slowly than benzene in all other electrophilic aromatic
substitution reactions. Thus, the nitro group is a deactivating group.
A given substituent group is either activating in all electrophilic aromatic substitution re-
actions or deactivating in all such reactions. Whether a substituent is activating or deactivat-
16.5 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF SUBSTITUTED BENZENES 769
ing is shown in the last column of Table 16.2, p. 763. In this table the most activating sub-
stituent groups are near the top of the table. Three generalizations emerge from examining this
table.
- All meta-directing groups are deactivating groups.
- All ortho, para-directing groups except for the halogens are activating groups.
- The halogens are deactivating groups.
Thus, except for the halogens, there appears to be a correlation between the activating and di-
recting effects of substituents.
In view of this correlation, it is not surprising that the explanation of activating and deacti-
vating effects is closely related to the explanation for directing effects. A key to understand-
ing these effects is the realization that directing effects are concerned with the relative rates of
substitution at different positions of the same compound, whereas activating or deactivating
effects are concerned with the relative rates of substitution of different compounds—a substi-
tuted benzene compared with benzene itself. As in the discussion of directing effects, we con-
sider the effect of the substituent on the stability of the intermediate carbocation, and we then
apply Hammond’s postulate by assuming that the stability of this carbocation is related to the
stability of the transition state for its formation.
Two properties of substituents must be considered to understand activating and deactivat-
ing effects. First is the resonance effect of the substituent. The resonance effect of a sub-
stituent group is the ability of the substituent to stabilize the carbocation intermediate in elec-
trophilic substitution by delocalization of electrons from the substituent into the ring. The
resonance effect is the same effect responsible for the ortho, para-directing effects of sub-
stituents with unshared electron pairs, such as LOCH 3
and halogen (colored structure in Eq.
16.29, p. 764). We can summarize this effect with the following two of the four resonance
structures for the carbocation intermediate in Eq. 16.29.
The second property is the polar effect of the substituent. The polar effect is the tendency
of the substituent group, by virtue of its electronegativity, to pull electrons away from the ring.
This is the same effect discussed in connection with substituent effects on acidity (Sec. 3.6C).
When a ring substituent is electronegative, it pulls the electrons of the ring toward itself and
creates an electron deficiency, or positive charge, in the ring. In the carbocation intermediate
of an electrophilic substitution reaction, the positive end of the bond dipole interacts repul-
sively with the positive charge in the ring, thus raising the energy of the ion:
|
OCH
3
E H
s
repulsive interaction
the polar effect of the
methoxy group destabilizes
the carbocation
d –
d +
the resonance effect of the
methoxy group stabilizes
the carbocation
(two of the four important
resonance structures)
|
OCH
3
E H
e
S
|
OCH
3
s
E H
16.5 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF SUBSTITUTED BENZENES 771
reaction coordinates
r
D G 8
‡
benzene
(a)
`
"
L
H
E
r
|
|
|
(b)
faster reaction
than benzene
slower reaction
than benzene
"
L
H
E
r
M
CH 3
O 21
M
CH 3
O 21
(c)
M
CH 3
O 21
`
less stable
carbocation
intermediate
more stable
carbocation
intermediate
carbocation
intermediate
H E
$)
CH
3
O 21
`
M
D G 8
‡
anisole
(para)
D G 8
‡
anisole
(meta)
STANDARD FREE ENERGY
Figure 16.6 Basis of the activating effect of the methoxy group on electrophilic aromatic substitution in
anisole. (a) The energy barrier for substitution of benzene by an electrophile E
|
. (b) The energy barrier for substi-
tution of anisole by E
|
at the para position. (c) The energy barrier for substitution of anisole by E
|
at the meta po-
sition. (Notice that the diagrams for parts (b) and (c) are the same as parts (a) and (b) of Fig. 16.5, p. 765.) The sub-
stitution of anisole at the para position is faster than the substitution of benzene; the substitution of anisole at
the meta position is slower than the substitution of benzene.The methoxy group is an activating group because
the observed reaction of anisole—substitution at the para position—is faster than the substitution of benzene.
Cl C O C
CH
3
overlap of carbon 2 p
and chlorine 3 p orbitals
(b)
overlap of carbon and oxygen 2 p orbitals
(a)
Figure 16.7 The overlap of carbon and oxygen 2 p orbitals, which is shown in part (a), is more effective than the
overlap of carbon 2 p and chlorine 3 p orbitals, shown in part (b), because orbitals with different quantum numbers
have different sizes and different numbers of nodes.The blue and green parts of the orbitals represent wave peaks
and wave troughs, respectively. Bonding overlap occurs only when peaks overlap with peaks and troughs overlap
with troughs.
772 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES
that alkyl groups activate substitution at all ring positions, but they are ortho, para directors be-
cause they activate ortho, para substitution more than they activate meta substitution (Eqs.
16.31 and 16.32, p. 766).
Finally, consider the deactivating effects of meta-directing groups such as the nitro group.
Because a nitro group has no electron-donating resonance effect, the polar effect of this elec-
tronegative group destabilizes the carbocation intermediate and retards electrophilic substitu-
tion at all positions of the ring. The nitro group is a meta-directing group because substitution
is retarded more at the ortho and para positions than at the meta positions (Eqs. 16.33 and
16.34, p. 766). In other words, the meta-directing effect of the nitro group is not due to selec-
tive activation of the meta positions, but rather to greater deactivation of the ortho and para po-
sitions. For this reason, the nitro group and the other meta-directing groups might be called
meta-allowing groups.
PROBLEMS
16.25 Draw reaction-free energy profiles analogous to that in Fig. 16.6 in which substitution on
benzene by a general electrophile E
|
is compared with substitution at the para and meta po-
sitions of (a) chlorobenzene; (b) nitrobenzene.
16.26 Explain why the nitration of anisole is much faster than the nitration of thioanisole under the
same conditions.
16.27 Which should be faster: bromination of benzene or bromination of N , N -dimethylaniline?
Explain your answer carefully.
C. Use of Electrophilic Aromatic Substitution in Organic Synthesis
Both activating/deactivating and directing effects of substituents can come into play in plan-
ning an organic synthesis that involves electrophilic substitution reactions. The importance of
directing effects is illustrated in Study Problem 16.2.
Study Problem 16.
Outline a synthesis of p -bromonitrobenzene from benzene.
Solution The key to this problem is whether the bromine or the nitro group should be the first
ring substituent introduced. Introduction of the bromine first takes advantage of its directing effect
in the subsequent nitration reaction:
(16.35)
Br 2
c
Br
L
bromobenzene
NO 2
c
Br
L L
p -bromonitrobenzene
HNO 3
H 2
SO 4
c Fe
benzene
c
N(CH
3
)
2
L 2
N , N -dimethylaniline
c
SCH 3
L 2
2
thioanisole
c
OCH 3
L 2
2
anisole
774 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES
After the first bromination, the LOH and LBr groups direct subsequent brominations to dif-
ferent positions. The strong activating and directing effect of the LOH group at the ortho and
para positions overrides the weaker directing effect of the LBr group.
In other cases, mixtures of isomers are typically obtained.
You’ve just learned that the activating and directing effects of substituents must be taken
into account in developing the strategy for an organic synthesis that involves a substitution re-
action on an already-substituted benzene ring. The activating or deactivating effects of sub-
stituents in an aromatic compound also determine the conditions that must be used in an elec-
trophilic substitution reaction. The bromination of nitrobenzene, for example (Eq. 16.28,
p. 762), requires relatively harsh conditions of heat and a Lewis acid catalyst because the nitro
group deactivates the ring toward electrophilic substitution. The conditions in Eq. 16.28 are
more severe than the conditions required for the bromination of benzene itself, because ben-
zene is the more reactive compound. An even more dramatic example in the other direction is
provided by the bromination of mesitylene (1,3,5-trimethylbenzene), Mesitylene can be
brominated under very mild conditions, because the ring is activated by three methyl groups;
a Lewis acid catalyst is not even necessary.
(16.41)
2
CH
3
CH
3
H
3
C
i
M M
mesitylene
CH
3
CH
3
H
3
C
i
M M
Br
(80% yield)
0–10 °C
CCl 4
16.28 Predict the predominant product(s) from:
(a) monosulfonation of m -bromotoluene (b) mononitration of m -bromoiodobenzene
PROBLEM
(16.40)
4-chloro-3-nitrotoluene
(42%)
NO
2
CH
3
Cl
i
M
4-chloro-2-nitrotoluene
(58%)
NO
2
CH
3
Cl
i
M
HONO 2
4-chlorotoluene
Cl
CH
3
Cl directs ortho
CH
3
directs ortho
i
3 Br (16.39)
2
OH
i
phenol
OH
i
M M
Br
Br
Br
2,4,6-tribromophenol
quantitative;
virtually instantaneous
H
2
O
STUDY GUIDE LINK 16.
Reaction Conditions
and Reaction Rate
16.5 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF SUBSTITUTED BENZENES 775
A similar contrast is apparent in the conditions required to sulfonate benzene and toluene. Sul-
fonation of benzene requires fuming sulfuric acid (Eq. 16.12, p. 755). However, because
toluene is more reactive than benzene, toluene can be sulfonated with concentrated sulfuric
acid, a milder reagent than fuming sulfuric acid.
Another very important consequence of activating and deactivating effects is that when a
deactivating group—for example, a nitro group—is being introduced by an electrophilic sub-
stitution reaction, it is easy to introduce one group at a time, because the products are less re-
active than the reactants. Thus, toluene can be nitrated only once because the nitro group that
is introduced retards a second nitration on the same ring. The following three equations show
the conditions required for successive nitrations. Notice that each additional nitration requires
harsher conditions.
Fuming nitric acid (Eq. 16.43c) is an especially concentrated form of nitric acid. Ordinary nitric acid
contains 68% by weight of nitric acid; fuming nitric acid is 95% by weight nitric acid. It owes its
name to the layer of colored fumes usually present in the bottle of the commercial product. Fuming
nitric acid is a much harsher (that is, more reactive) nitrating reagent than nitric acid itself.
In contrast, when an activating group is introduced by electrophilic substitution, the prod-
ucts are more reactive than the reactants; consequently, additional substitutions can occur eas-
ily under the conditions of the first substitution and, as a result, mixtures of products are ob-
tained. This is the situation in Friedel–Crafts alkylation. As noted in the discussion of Eq.
16.19 (p. 758), one way to avoid multiple substitution in such cases is to use a large excess of
O Lv L (16.43c)
2
N
NO
2
NO
2
CH
3
2,4,6-trinitrotoluene
“TNT”
(90% yield)
O L v L
2
N CH
3
NO
2
2,4-dinitrotoluene
50 g
170 g fuming HNO
3
H
2
SO
4
(680 g)
120 °C, 5 h
(16.43b)
O Lv L
2
N
NO
2
CH
3
2,4-dinitrotoluene
(90% yield)
O L v L
2
N CH
3
4-nitrotoluene
50 g
HNO 3
(30 g)
H 2
SO 4
(200 g)
70 °C, 30 min
(16.43a)
c
CH
3
L
toluene
50 g
ortho isomer
c
CH
3
L L
O
2
N
4-nitrotoluene
HNO 3
(30 g)
H
2
SO
4
(30 g)
50 °C, 1 h
(16.42) H
2
SO
4
c H
3
C
L
+ SO
3
H
cL H
3
C
L
H
2
+ O
toluene
p -toluenesulfonic acid
