Chem 2124 unit 2c f2011

REACTIONS OF AROMATIC COMPOUNDS
Electrophilic Aromatic Substitution:
The mechanism of many reactions of aromatic compounds
are explained by minor variations of electrophilic aromatic
substitution.
Recall that there are clouds of pi electrons above and below
the sigma bonds of a benzene ring. These pi electrons are in
a stable aromatic system. These pi electrons make the
aromatic ring an electron rich materials. These pi electron
are available to attach by strong electrophiles to give a
carbocation intermediate.

Step 1: Attack on the electrophile forms the sigma complex.
Step 2: Loss of a proton gives the substitution product.

Show the mechanism for the following reaction.
+ Cl2 + AlCl3
Hint: AlCL3 is a Lewis acid (an electron pair acceptor). Many substitution reactions
involving an aromatic ring require a Lewis acid catalyst.

There are two things that must be considered when predicting
the products of an electrophilic aromatic substitution reaction.
1. Identify the electrophilic species (what is the electrophile)?
2. What are the substituents groups that are already on the
aromatic ring? (substituent effects)

halogenation
+ X2
Lewis acid
Lewis acids: AlX3 , FeX3
X2 = Br2 , CL2
+ HX
X

halogenation
Iodination requires an acidic oxidizing agent, like nitric acid, which oxidizes
the iodine to an iodonium ion.
I2 + 2H+ + HNO3 2I+ + NO2 + H2O
H
+ I+

Nitration
The nitration of benzene is conveniently done using a mixture
of nitric acid and sulfuric acid. The sulfuric acid is a catalyst
which reacts with nitric acid to generate the nitronium ion
(NO+). The use of sulfuric acid allows the reaction to take
2
place at a faster rate and at a lower temperature.
+ HNO3
H2SO4
+ H2O
NO2
85%

Nitration
Draw the mechanism for the nitration of benzene.
+ HNO3
H2SO4
+ H2O
NO2

Reduction of nitroaromatics
Nitration of an aromatic ring is often the first step in a two step
process that is used to add an amine group to an aromatic ring. The
reduction of the nitro group is easily accomplished by treatment with
a metal and dilute acid.
Zn, Sn, or Fe
NO2 R R NH2
HCl (aq)
It is common in organic synthesis to add a functional group to a substrate
and then to convert the group to the the desired group.

Sulfonation of benzene
This reaction is done using fuming sulfuric acid (7% SO3 in H2SO4).

desulfonation of benzene
Under what conditions do you think this reaction would be run?

Exchange reactions of benzene
H
H
H
H
H
H
D
D
D
D
D
D
large excess
D2SO4 / D2O
Write a mechanism for this reaction.

Effect of ring substituents
Mono-nitration of benzene gives only a single product,
while mono-nitration of toluene can give three different
products.
CH3 CH3 CH3 CH3
HNO3
H2SO4
o-nitrotoluene m-nitrotoluene
p-nitrotoluene
(60%) (4%)
(36%)
NO2
NO2
NO2

There are two interesting observations that can be made
when comparing the nitration of benzene vs toluene.
The first is that the reaction rate for toluene is ~25 times
faster then benzene. The methyl group activated the ring
toward electrophilic substitution. Methyl is an activating
group.
The second is the distribution of products. If all of the
positions on the ring were equivalent you would expect a
2:2:1 ratio of the ortho, metha and para products.

CH3
ortho ortho
meta meta
para
There are two ortho positions, two meta positions
and one para position.

Nitration of toluene preferentially occurs at the positions
ortho and para to the methyl group. The methyl group is
referred to as being an ortho, para-director.
The presences of the methyl group on the aromatic ring has
two effects. It affects reaction rates and where substitution
occurs at on the ring.

You must be able to do the following:
1. Know how different functional groups are added to an
aromatic ring.
2. Know how different substituent groups affect the reactivity
of an aromatic ring.
3. Know how different substituent groups affect where
substitution will occur.

The results seen here for toluene (methylbenzene) are general
for all mono-alkylbenzenes when undergoing electrophilic
aromatic substitution reactions.
The sigma complexes formed ortho and para to the alkyl group
are more stable then the meta complex because the ortho and
para complex have resonance forms with tertiary carbocations.
This effect is called inductive stabilization because the alkyl
group is donating electron density to the intermediate through
the sigma bond.

Effect of substituents with non-bonding electrons
X: X:
+ E+ +
E
When a substituent group has a non-bonding pair of electrons
on the atom directly bonded to the ring, the sigma complex
initially formed during an electrophilic substitution reaction
can be resonance stabilized by the non-bonding electrons.

The affect of resonance stabilization by substituents with non-bonding
electrons on reaction rates can be very large. In the
case of anisole the rate of nitration is ~10,000 time faster than
benzene and ~ 400 times faster then toluene. This type of
stabilization is also called resonance donating and pi-donating.
Substituents with non-bonding electrons are ortho/para directors.
They may be either activating or deactivating.

Recall that the bromination of benzene required a Lewis
catalyst. However, with strong activating substituent like the
amino group in aniline the reaction occurs with multiply
additions of bromine without a catalyst. Where did
substitution occur at and what happens if you don’t have the
bicarbonate in the reaction?

Activating Ortho/Para directors

Deactivating meta-directing substituents
We have seem how the presence of some substituents can
greatly enhance the reactivity of an aromatic ring compared to
benzene. We will now look at substituents that deactivate the
aromatic ring toward electrophilic attack.
In electrophilic aromatic substitution reactions nitrobenzene is
~100,000 less reactive than benzene. In addition to
deactivation of the ring the substitution occurs at the meta
position.

In electrophilic aromatic substitution reactions nitrobenzene is
~100,000 less reactive than benzene. In addition to
deactivation of the ring the substitution occurs at the meta
position.
NO2 NO2 NO2 NO2
HNO3, 100 C
H2SO4
ortho (6%)
meta (93%)
para (0.7%)
NO2
+ +
NO2
NO2

Why does the nitro group deactivate the ring in electrophilic
aromatic substitution reactions? Why is the nitro group a meta
director?
To answer these questions we need to look at the intermediates
that are formed during the reaction.

Structural characteristics of Meta-Directing
Deactivators
1. The atom attached to the aromatic ring will have
a formal positive charge or a partial positive
charge.
2. Electron density is withdrawn inductively along
the sigma bond, so the ring is less electron-rich
than benzene. Destabilizes the sigma complex.

Halogenated aromatics
Halogenated aromatic compounds under go electrophile
substitution ortho and para to the halogen. This is an
expected result since halogens have non-bonding
electrons that can resonance stabilize the intermediate
sigma complex .
Halogens are orhto/para directors but unlike other ortho/para
directors, halogens deactivate the aromatic ring toward
electrophilic substitution reactions. Why are halogens
deactivators?`

Ortho and para attacks produce a bromonium ion
and other resonance structures.

In the meta position there is no stabilization of the
sigma complex.

Summary of substituent effects
What about multiple substituents?

Effects of multiple substituents
 When two or more substituents are present on an aromatic ring a combined
effect is observed in subsequent reactions.
 In many cases it is easy to predict the effects of multiple substituent
groups because the individual effects are mutually supporting of each
other.
 In cases were there is a conflict in the directing effects of the substituent
groups it can more difficult to predict what products will be produced.

Effects of multiple substituents
 When dealing with multiple substituents activating groups are
generally stronger directors than deactivating groups.
1. Strong activating ortho, para-directors that stabilize the transition state
through resonance. i.e. –OH, –OR
2. Activating ortho, para-directors. i.e. alkyl groups and halogens
3. Deactivating meta directors.

Friedel-Crafts Alkylation
What is the mechanism?
Hint: Think about halogenation of an aromatic ring.

Rearrangement of the alkylating agent is possible and is limitation
of Friedel-Crafts alkylation. As a result, only certain alkylbenzenes
can be made using the Friedel-Crafts alkylation.

Multiple alkylation is a limitation and as a result mixtures of
products are common.

Limitations of Friedel-Crafts Alkylation:
1. Only works with benzene and activated benzene derivatives.
Fails with strong deactivating groups on the ring.
2. Rearrangement of the alkylating agent can occur, limiting
the
types of alkyl benzenes that can be produced.
3. Multiple alkylation's can occur resulting in undesired side
products.

Friedel-Crafts Acylation
A deactivating group

Mechanism Friedel-Crafts Acylation
an electrophile species

Friedel-Crafts Acylation
1. The reaction require a full equivalent of Lewis acid, because
the ketone product of the reaction will complex the Lewis acid.
2. The actual electrophilic species is thought to be a bulky complex, such as
R-C+=O,AlCl4
-. As a result of the size of the electrophile, para
substitution is predominate when the substrate contains an ortho/para
director.
3. The addition of the acyl group deactivates the ring toward additional
substitution reactions.

Friedel-Crafts Alkylation vs Acylation
Alkylation:
Can not be used with strongly
deactivated derivatives.
Carbocations involved in the
alkylation undergo rearrangement.
Multiply substitution is common.
Acylation:
Same
Acylium ions are not prone to rearrange.
Product is deactivated, limiting multiply
substitutions.

Clemmensen Reduction
R
O
H H
R
Zn(Hg)
aq HCl

Cl
Acylation followed by reduction.
O
+
AlCl3
O
O
Zn(Hg)
HCl (aq)

Gatterman-Kock Formylation
CH2CH3
+ CO + HCl
CuCl
AlCl3
O H
CH2CH3
The above reaction allow for the formylation of aromatic compounds. The
electrophile is the formyl cation [H-C+=O]. The insitu generation of the
electrophile is required because formyl chloride (HCOCl) is unstable. See
page 779.

Cl
O
+
O
HNO3
H2SO4
?
? ?
?
O
H
?
?

Nucleophilic aromatic substitution
 Nucleophilic substitution involves the attack of and electron
rich group on the electron rich aromatic ring with subsequent
lose of a leaving group and it’s electrons.
 There are two mechanism that are seen with nucleophilic substitution
reactions.
 Addition-Elimination: requires strong electron withdrawing groups and a
leaving group ortho or para to the electron withdrawing substituents.
 Elimination-Addition: requires a good leaving group and the use of a very
strong base or harsh reaction conditions(>200°C).

Nitro groups ortho and para to the halogen stabilize the intermediate (and the transition state leading to it).
Without electron withdrawing groups in these positions, formation of the negatively charged sigma
complex is unlikely.

F
NO2
NO2
H2N CH C
R
O
+ NH peptide
Sanger Reagent
?
6 M HCl / heat
?
Any thing interesting about the leaving group?

Elimination-addition mecchanism for Nucleophilic Aromatic Substitution
Br
CH3
NH2
CH3
CH3
NH2
+
NaNH2
NH3, -33°C
Notice that two products are produced from this reaction. The first is as
expected with the bromine being replaced by an –NH2. The second
product has the new substituent in an adjacent position.

Benzyne Mechanism for Nucleophilic Aromatic Substitution
The base that is used here is sodium amide (NaNH2).

Benzyne Mechanism for Nucleophilic Aromatic Substitution
What stereochemical issues are there with this mechanism?

Chlorination
+ 3 Cl2
heat, pressure
or hv
There are eight isomer possible. The most important isomer
is lindane, an insecticide.

Hydrogenation
+ 3 H2
catalyst
1000 psig
100% cyclohexane
The catalyst that are commonly used are Pt, Pd, Ni, Ru, or Rh.
The temperature and pressure can vary considerably depending
on the catalyst used.

Burch Reduction

Reactions of side chains (oxidation with permanganate)
The alkyl groups on an aromatic ring can be converted to
carboxylic acids by oxidation with permanganate or
chromic acid.
CH2CH3 KMnO4, H2O or OH- CO2H
Heat
or Na2Cr2O7, H2SO4
If there are addition substituents on the ring they need to be
resistant to oxidation. i.e. halo or nitro groups

Reactions of side chains (oxidation with permanganate)
CH3
CH3
CH3
CH3
Br

Reactions of side chains (halogenation)

Reactions of side chains (halogenation)
Benzylic halides are very reactive in both SN1 and SN2
reactions.
Br
CHCH3
CH3O-CHCH3
Br
(CH3)3N
heat

Chem 2124 unit 2c f2011

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