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Reactions of Aromatic Compounds

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Chapter 15<br />

<strong>Reactions</strong> <strong>of</strong> <strong>Aromatic</strong> <strong>Compounds</strong><br />

Benzenoid hydrocarbons are <strong>of</strong>ten called arenes. The symbol used<br />

to represent the aryl group<br />

is Ar, so arene compounds are ArH<br />

and substituted arenes are ArX.<br />

Ar- ArH ArX<br />

Aryl group Generic arene Substituted arene<br />

?


Electrophilic <strong>Aromatic</strong> Substitution<br />

This most characteristic reaction <strong>of</strong> arenes may be used to introduce<br />

a variety <strong>of</strong> substitutents into the structure:<br />

Ar-H + E + Ar-E + H +<br />

Electrophile<br />

For the case <strong>of</strong> benzene,<br />

+ E +<br />

Electrophile<br />

E<br />

+ H +<br />

Note: In these reactions, an electrophile substitutes for an H on the<br />

aromatic ring. This substitution contrasts with the addition <strong>of</strong><br />

an electrophile to an alkene. In addition to an alkene, the<br />

weaker π-bond is replaced by stronger σ-bonds, but this does<br />

not occur with an arene because the large stabilizing<br />

resonance energy <strong>of</strong> the aromatic ring would be lost.


Examples <strong>of</strong> Electrophilic <strong>Aromatic</strong> Substitution <strong>Reactions</strong><br />

X 2, FeX 3<br />

X = Cl, Br<br />

HONO 2<br />

H 2SO 4<br />

SO 3<br />

H 2SO 4<br />

RCl<br />

AlCl 3<br />

O<br />

RCCl<br />

=<br />

AlCl 3<br />

X<br />

NO 2<br />

Halogenation<br />

Nitration<br />

SO 3H<br />

Sulfonation<br />

R Friedel-Crafts<br />

Alkylation<br />

O<br />

= C<br />

R<br />

Friedel-Crafts<br />

Acylation<br />

These reactions are<br />

commonly used<br />

synthetic procedures<br />

for modifying arenes.<br />

They proceed by a<br />

general mechanism<br />

initiated by addition <strong>of</strong><br />

an electrophile E + to<br />

the aromatic π-system,<br />

forming a nonaromatic<br />

carbocation<br />

intermediate called an<br />

arenium ion.


Description <strong>of</strong> Mechanism Using Resonance Structures<br />

Step 1: Attack by the Electrophile<br />

Two π-electrons form a σ-bond to the incoming electrophile yielding<br />

a delocalized carbocation intermediate called an arenium ion.<br />

δ<br />

E A<br />

+ δ -<br />

- A:<br />

H<br />

E<br />

+ +<br />

H<br />

E<br />

+<br />

-<br />

These resonance structures show the distribution<br />

<strong>of</strong> positive charge in the arenium ion.<br />

The arenium ion is non-aromatic, but it is<br />

reasonably stable because <strong>of</strong> charge dispersal<br />

over the carbons ortho and para to the site <strong>of</strong><br />

attachment <strong>of</strong> the electrophile.<br />

δ+<br />

H<br />

E<br />

δ+ δ+<br />

H<br />

E


Step 2: Deprotonation <strong>of</strong> the Arenium Ion<br />

and Re-aromatization<br />

H<br />

E<br />

+<br />

+ A: - E<br />

+ H-A<br />

The Lewis base that attacks and removes the proton<br />

may, as shown, be the conjugate base <strong>of</strong> the electrophile<br />

or some other Lewis base that may be present.


Free-Energy Diagram for an<br />

Electrophilic <strong>Aromatic</strong> Substitution Reaction<br />

The much larger energy <strong>of</strong> activation requirement for<br />

Step 1 makes it the slow, rate-determining step.


Halogenation <strong>of</strong> Benzene<br />

Halogenation <strong>of</strong> benzene and other arenes is one <strong>of</strong> the most common<br />

ways to functionalize aromatics. The reaction <strong>of</strong> benzene with Cl 2 or<br />

Br 2 requires catalysis by a Lewis acid. (Benzene, in contrast to alkenes,<br />

will not decolorize a solution <strong>of</strong> Br 2 in CCl 4.)<br />

Commonly employed Lewis acids are the iron halides, preformed or<br />

generated in situ:<br />

2 Fe + 3 X 2<br />

+ Cl 2<br />

+ Br 2<br />

FeCl 3<br />

FeBr 3<br />

2 FeX 3<br />

Cl<br />

+ HCl<br />

Chlorobenzene (~90%)<br />

Br<br />

+ HBr<br />

Bromobenzene (~75%)


Role <strong>of</strong> the Catalyst<br />

The Lewis acid complexes with and polarizes the X 2 producing a more<br />

reactive electrophile capable <strong>of</strong> disrupting the rather stable aromatic<br />

π-system in benzene and other arenes.<br />

:Br-Br:<br />

: :<br />

: :<br />

Highly polarizable<br />

but nonpolar<br />

+ FeBr 3<br />

:Br-Br-FeBr 3<br />

: :<br />

+<br />

: :<br />

-<br />

A polar complex<br />

The complex transfers a positive bromide ion to the π-system <strong>of</strong> the<br />

arene. The effective electrophile in the bromination reaction is<br />

sometimes written as Br + , formed as shown below, but direct<br />

involvement <strong>of</strong> the complex is more likely.<br />

+<br />

:Br-Br-FeBr 3<br />

: :<br />

: :<br />

-<br />

:Br +<br />

: :<br />

-<br />

+ FeBr4


Mechanism:<br />

Step 1: Electrophilic Attack<br />

:Br--Br--FeBr3 -<br />

- FeBr4 : :<br />

+<br />

: :<br />

-<br />

Electrophile<br />

+ H<br />

Br<br />

+<br />

H<br />

Br<br />

Arenium ion<br />

Step 2: Deprotonation and Re-aromatization<br />

H<br />

Br<br />

+<br />

:Br-FeBr 3<br />

: :<br />

-<br />

Lewis base<br />

Br<br />

+ HBr + FeBr 3<br />

Catalyst is<br />

reformed<br />

H<br />

Br<br />

+


Chlorination <strong>of</strong> Benzene<br />

Chlorination <strong>of</strong> benzene proceeds by a mechanism parallel with that<br />

for bromination, a complex <strong>of</strong> FeCl 3 and Cl 2 providing the effective<br />

electrophile [Cl + ].<br />

Step 1: Electrophilic Attack<br />

:Cl--Cl--FeCl 3<br />

: :<br />

+<br />

: :<br />

Fluorination <strong>of</strong> Benzene<br />

-<br />

+<br />

H<br />

Cl<br />

-<br />

+ FeCl4 Direct reaction <strong>of</strong> F 2 with benzene is very exothermic and proceeds<br />

explosively. Special procedures are required to carry out this reaction<br />

safely .<br />

Fluorobenzene and other mon<strong>of</strong>luoroarenes may be synthesized<br />

indirectly by way <strong>of</strong> aryl diazonium ions, which will be considered<br />

later.


Iodination <strong>of</strong> Benzene<br />

Direct iodination <strong>of</strong> benzene with I 2 is a very slow reaction because<br />

<strong>of</strong> the unfavorable bond energy changes, but it can be achieved in the<br />

presence <strong>of</strong> an oxidizing agent.<br />

+ I 2<br />

HNO 3<br />

Alternatively, iodobenzene and other iodoarenes may be prepared<br />

indirectly by way <strong>of</strong> aryl diazonium ions.<br />

I<br />

(86%)<br />

Reactivity in the Halogenation <strong>of</strong> Benzene<br />

Fluorination > Chlorination > Bromination > Iodination<br />

Explosively reactive<br />

Very slow


Nitration <strong>of</strong> Benzene<br />

Benzene reacts only slowly with hot concentrated nitric acid to give<br />

nitrobenzene. The reaction is much faster in a mixture <strong>of</strong> concentrated<br />

nitric acid (pK a = -1.4) and concentrated sulfuric acid, a much<br />

stronger acid (pK a = -9).<br />

+ HNO 3 + H 2SO 4<br />

Concentrated acids<br />

~ 50 o C<br />

NO 2<br />

+ H 3O + + HSO 4 -<br />

Nitrobenzene (~ 85%)


Mechanism <strong>of</strong> Nitration<br />

(1) Generation <strong>of</strong> the Electrophile<br />

Nitric acid undergoes reversible dehydration in the presence <strong>of</strong><br />

concentrated sulfuric acid producing the nitronium ion, a strong<br />

electrophile.<br />

H-O<br />

: :<br />

: O:<br />

N<br />

+<br />

=<br />

pK a = -1.4<br />

+<br />

H-O<br />

H<br />

:<br />

O:<br />

-<br />

: :<br />

: O:<br />

N<br />

+<br />

=<br />

O:<br />

-<br />

: :<br />

+ H-OSO 3H<br />

pK a = -9<br />

H 2O +<br />

+<br />

H-O<br />

H<br />

:<br />

: O:<br />

N<br />

:<br />

O:<br />

: O:<br />

N<br />

=<br />

+<br />

=<br />

+<br />

=<br />

Nitronium ion<br />

O:<br />

-<br />

: :<br />

+ -OSO3H


(2) Electrophilic Attack<br />

+<br />

: O:<br />

N<br />

: O:<br />

+<br />

=<br />

=<br />

slow step<br />

(3) Deprotonation and Re-aromatization<br />

H O<br />

+<br />

O<br />

+<br />

H<br />

O-H<br />

+<br />

N=<br />

:<br />

: :<br />

:<br />

: -<br />

::<br />

H + O<br />

+<br />

N=<br />

:<br />

: :<br />

:<br />

O<br />

Arenium ion<br />

Remember, the nitro group is zwitterionic,<br />

and resonance stabilized: :O: -<br />

N+<br />

:<br />

O:<br />

: -<br />

etc.<br />

NO 2<br />

+ H 3O +<br />

:O:<br />

N<br />

+<br />

O<br />

=<br />

:<br />

: :<br />

-


Sulfonation <strong>of</strong> Benzene<br />

Benzene reacts with fuming sulfuric acid (concentrated sulfuric acid<br />

plus added SO3, the actual electrophile) to give benzenesulfonic acid.<br />

Fuming H2SO4 25 o O SO3H S=O<br />

O<br />

C<br />

. . .<br />

.<br />

+<br />

Benzenesulfonic acid<br />

In concentrated sulfuric acid alone, an equilibrium-limited supply <strong>of</strong><br />

SO 3 effects slow sulfonation.<br />

(1) Generation <strong>of</strong> the Electrophile<br />

:O:<br />

H-O-S-O-H<br />

: :<br />

= = :O:<br />

: :<br />

=<br />

: :<br />

:O:<br />

+ H-O-S-O-H<br />

: :<br />

= = :O:<br />

:O:<br />

+<br />

H-O-S-O-H<br />

H<br />

:<br />

=<br />

= = :O:<br />

: :<br />

: :<br />

Sulfur trioxide<br />

: :<br />

:O:<br />

- +<br />

:O:<br />

H-O-S-O: + H-O-S-O-H<br />

H<br />

: :<br />

= = :O:<br />

: :<br />

:<br />

H3O + O<br />

+ S=O<br />

O<br />

.. . =<br />

: :<br />

=<br />

: :<br />

= = :O:<br />

Sulfur trioxide<br />

: :


(2) Electrophilic Attack<br />

+<br />

O<br />

S=O<br />

O<br />

. . .<br />

.<br />

: :<br />

: :<br />

slow<br />

(3) Deprotonation and Re-aromatization<br />

:<br />

H<br />

S<br />

+<br />

:O:<br />

=<br />

=<br />

O:<br />

-<br />

O:<br />

: :<br />

:O:<br />

-<br />

+ :O-S-O-H<br />

: :<br />

= = :O:<br />

: :<br />

Hydrogen sulfate<br />

fast<br />

H<br />

S<br />

+<br />

:O:<br />

:<br />

O:<br />

=<br />

=<br />

-<br />

O:<br />

: :<br />

Arenium ion<br />

:O:<br />

S O:<br />

.<br />

. . O<br />

.<br />

= =<br />

: :<br />

Benzenesulfonate ion<br />

etc.<br />

- + H2SO 4


(4) Acid-Base Equilibrium<br />

:O:<br />

S O:<br />

.<br />

. O<br />

.<br />

= =<br />

-<br />

: :<br />

Synthetic Applications<br />

+ H 3O<br />

fast<br />

+ S<br />

:O:<br />

O-H<br />

.<br />

.<br />

. O.<br />

= =<br />

: :<br />

Benzenesulfonic acid<br />

pKa = 0.699<br />

+ H 2O<br />

Although introduction <strong>of</strong> a sulfonic acid group is generally <strong>of</strong> more<br />

limited interest than other electrophilic substitution reactions, the<br />

reversibility <strong>of</strong> sulfonation leads to its use in synthetic strategy.<br />

Heating arylsulfonic acids in dilute sulfuric acid removes the sulfonic<br />

acid function.<br />

SO 3H<br />

+ H 2O<br />

heat<br />

dilute H 2SO 4<br />

+ H 2SO 4


Friedel-Crafts Alkylation<br />

Discovered in 1877 by French chemist Charles Friedel and his American<br />

collaborator James Crafts, this alkylation reaction (one introducing an<br />

alkyl group) and the related acylation reaction (one introducing an acyl<br />

group) are among the most useful synthetic reactions.<br />

Alkylation <strong>of</strong> an Arene<br />

+ R-X<br />

AlCl 3<br />

Alkyl halide Alkylbenzene<br />

R<br />

+ HX<br />

This reaction requires a Lewis acid catalyst, typically aluminum<br />

chloride, AlCl 3. Many variations <strong>of</strong> the Friedel-Crafts alkylation<br />

reaction have been developed. All proceed by similar mechanisms.


A Mechanism for the Alkylation Reaction<br />

The Lewis acid catalysts generally required in Friedel-Crafts<br />

reactions promote formation <strong>of</strong> strong electrophiles.<br />

(1) Generation <strong>of</strong> the Electrophile<br />

R-Cl:<br />

: :<br />

Lewis base<br />

+ AlCl 3<br />

Lewis acid<br />

+<br />

R-Cl-AlCl 3<br />

: :<br />

-<br />

Complex<br />

With 1 o halides, the complex itself, acting as an R + transfer agent,<br />

reacts with the arene.<br />

With 2 o and 3 o alkyl halides, dissociation to carbocation intermediates<br />

seems to occur, and the resulting R + species react with the arene.<br />

+<br />

R-Cl-AlCl 3<br />

: :<br />

-<br />

R + + AlCl -<br />

4


(2) Electrophilic Attack<br />

+<br />

or<br />

+<br />

R-Cl-AlCl 3<br />

: :<br />

-<br />

+ R + AlCl 4 -<br />

H<br />

R<br />

+<br />

(3) Deprotonation and Re-aromatization<br />

H<br />

R<br />

+<br />

:Cl:<br />

+ :Cl -<br />

Al<br />

: : : :<br />

:Cl<br />

:<br />

Lewis base<br />

Cl:<br />

: :<br />

Arenium ion<br />

R<br />

Alkylbenzene<br />

etc. + AlCl 4 -<br />

+ HCl + AlCl 3<br />

Regenerated<br />

catalyst


Evidence for Carbocation Intermediates<br />

Skeletal rearrangement is observed in Friedel-Crafts alkylation<br />

reactions when concurrent change to a more stable carbocation can<br />

occur.<br />

+ CH 3CH 2CH 2Br<br />

AlCl 3<br />

CH3 CH<br />

CH3 Propyl bromide Isopropylbenzene<br />

It is believed rearrangement occurs during reversible<br />

dissociation to a short-lived carbocation:<br />

+ -<br />

CH3CH2CH2-Br-AlCl3 Complex 1<br />

+<br />

CH3CH2CH2 +<br />

CH3CHCH3 + HBr<br />

+ AlBrCl 4<br />

+ -<br />

(CH3) 2CH-Cl-AlBrCl2 Complex 2


Other Alkylation Methods<br />

Any reaction that produces carbocations (or carbocation-like<br />

intermediates) may be used to alkylate benzene and other arenes.<br />

Examples<br />

1) Alkenes alkylate arenes in the presence <strong>of</strong> strong acids:<br />

+<br />

CH 3CH=CH 2<br />

Propene<br />

Via CH 3CH=CH 2<br />

HF<br />

HF<br />

0 o C<br />

CH3CHCH3 F - +<br />

Electrophile<br />

CH(CH 3) 2<br />

Isopropylbenzene<br />

(84%)


2) Alcohols alkylate arenes in the presence <strong>of</strong> strong acids:<br />

Via<br />

+<br />

Lewis base<br />

OH<br />

Cyclohexanol<br />

OH<br />

: :<br />

:F:<br />

:<br />

B<br />

:F F:<br />

: :<br />

BF 3<br />

60 o C<br />

: :<br />

Lewis acid<br />

Cyclohexylbenzene (56%)<br />

H<br />

+<br />

O<br />

:<br />

-<br />

BF3 -<br />

- HOBF 3<br />

+<br />

Electrophile

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