Chapter 17 – Reactions of Aromatic Compounds

• Electrophilic Aromatic Substitution

o General reaction - an electrophile replaces a hydrogen
 Electrons of pi system attack strong electrophile, generating resonance-
stabilized carbocation intermediate (sigma complex)

+
H H H
H
E+ E E
E
+ +
H H H
H

This is the slow step because it breaks up the aromaticity.

 Loss of a proton restores aromaticity
E E
H

+ H H

o Nitration
 Generation of the nitronium ion
O O
+ ·· H2SO4 + +
– N – N + O N O
O O H O O H

H
nitronium ion
 Electrophilic attack
 Loss of proton
o Sulfonation

O O H O
·· H2SO4 + +
H O S O H H O S O H H O S

O O O

 SO3 is also a powerful electrophile, but less so.

O O
S

 This reaction is reversible – Steam it!

o Halogenation
 Bromination
• Bromine reacts with FeBr3 to form the electrophile
 ·· Br + – Br
Br Br Fe Br Br Fe
Br Br
Br
Br

• Electrophilic attack
H Br
+ – Br
Br Br Fe H
Br +
Br
H H

• Loss of proton
Br Br
H

+ H H

 Chlorination
• Just like bromination, but you use chlorine and FeCl3
 Iodination
• Nitric acid is used as a reagent instead of a metal catalyst to
generate I+
o Friedel-Crafts Alkylation
 Alkyl choride + AlCl3 form a carbocation-like structure
H
+ _ +
Cl Cl-AlCl3 +
AlCl3

• It is important to note that this is likely still complexed with the

Lewis acid catalyst.
o You don’t really get the free carbocation, but it acts as
though you do.
 The carbocation acts as the electrophile
 Another way to alkylate
• When you start with an alkene and add a non-nucleophilic acid,
you can generate a carbocation.
H F
+

• This carbocation can now be the electrophile for Alkylation.

 HF

 Limitations of Friedel-Crafts Alkylation

• The carbocation can rearrange, so if you’re trying to add a straight
chain, this won’t work.
• Overalkylation
o We will see that alkyl groups are activators for this
reaction, so once you put one alkyl group on the addition
of a second alkyl group is even easier.
• Does not work on deactivated rings.
o Friedel-Crafts Acylation
 AlCl3 removes the Cl from an acid chloride
··
O O O +
_
+ O
AlCl3
Cl AlCl3 Cl
+

• This cation is resonance-stabilized, so you really do get it.

• This is called the acyllium ion and you do need to know its name!
 The carbonyl and alkyl group add to the ring
 How Friedel-Crafts Acylation gets over two of the limitations of Alkylation
• No rearrangement
• You will not overacylate, because once you put the acyl group on,
you have deactivated the ring
• It still does not work on deactivated rings.

Name of Reaction Reagents Electrophile What Replaces

the H

Nitration HNO3/H2SO4 Nitronium ion NO2

(NO2+)

Sulfonation H2SO4 SO3 or HSO3+ SO3H

 (SO3 sometimes)

Bromination Br2, FeBr3 “Br+” Br

Chlorination Cl2, FeCl3 “Cl+” Cl

Iodination I2, HNO3 I+ I

Alkylation RCl/AlCl3 or “R+” R

RBr/FeBr3

Acylation Acid chloride/ AlCl3 Acyllium ion O

··
O O+ R
+

• Substituent Effects
o We talked about Electron Donating Groups (EDGs) vs. Electron Withdrawing
Groups (EWGs) in Chapter 15 when talking about Diels-Alder
 Which category would make this reaction go faster?
• The slow step is the step where the electrons of the aromatic
system attack the electrophile, so having greater electron density
would make this slow step more likely to occur.
• As such, we will call EDGs “activating” and EWGs “deactivating”
o Halogens are weird. We’ll see why.
o Ortho, para-directors
 Ortho, para-directors are EDGs. Why?
 Think again about that sigma complex. Let’s look at brominating phenol.
H H H H
O +
O O O
H H + H H

Br Br Br Br
+ +

 Not only does having an EDG on the positively charged carbon stabilize by
induction, but when the EDG donates by resonance as well, you also get
an additional resonance form.
 A similar series of drawings can be made with para-addition
 When you halogenate at a meta position, the positive charge is never
stabilized by the substituent.
 H H H
O O O

+ +

H H H
Br Br + Br

 The majority of ortho, para-directing groups are activating as well.

• The exception is halogens.
o Meta-directors
 All meta-directors are deactivating EWGs.
 If you put an EWG at an ortho or para position, then you destabilize the
sigma complex.
– – –
O + O O + O O + O
N N N
Br Br + Br
H H H

+ +

o Multiple substituents
 When possible, make everyone happy.
o-, p-director O
O

Cl
Cl2, AlCl3

O
m-director O

 When you can’t make everyone happy, the most activating group
determines the placement of the electrophile.
• This makes sense because basically, the activating groups want
this reaction to happen, and the deactivating groups don’t want it
to happen.

• The further to the right below “wins” the fight over where to put
the new piece.
strong deactivators weak deactivators weak activators strong activators

-NO2
-NR3+ -OH
halogens alkyl groups
Carbonyls -OR

-CN -NH2

least activating most activating

• Side-chain reactions
o Clemmenson Reduction
 Chops off the carbonyl of ketones
O

Zn(Hg)

HCl (aq)

 Useful when you want to add a straight chain alkyl group.

• First, acylate, then reduce.

o Wolff-Kishner Reduction
 Overall, it’s the same reaction as Clemmenson reduction, just with
different reagents.

N2H4

-OH

o Benzylic Oxidation
 If the benzyllic carbon has at least one hydrogen on it, then treatment
with KMnO4 or chromic acid chops the rest of the chain off and turns the
first carbon into a carboxylic acid.
 O

H
KMnO4 O

O O

o Halogenation goes faster at benzylic positions.

o SN1/SN2 both go faster at benzylic positions.
• Synthesis questions
o When asked to synthesize something from benzene, the task can often seem
daunting.
o It’s important to remember that the more difficult synthesis questions of this
material fall into two categories:
 Two meta-directors ortho or para to each other
COOH
?

O2 N
• Step 1: Alkylate

Cl

AlCl3
• Step 2: Put the other piece on

HNO3

H2SO4
O2 N

• Step 3: Oxidize
 KMnO4 COOH

O2 N O2 N

 Two ortho-, para-directors meta to each other

• Step 1: Acylate

Cl O O

AlCl3

• Step 2: Put the other piece on

I2
O O

HNO3

• Step 3: Reduce

Zn(Hg)
O

HCl (aq)

I I

 For both of the above schemes, remember that there could be some
other intervening steps.
• Nucleophilic Aromatic Substitution
o Addition-Elimination
 Recognizing that you will be doing this reaction
• There has to be a halogen on the ring.
• Vigorous, basic conditions
• Strong EWG’s ortho and/or para to the halogen
• Only time where fluorine works best!
o Because fluorine is the most electronegative, it creates a
stronger partial positive at the carbon, so the nucleophilic
attack is more likely to happen.
 Overall Reaction
• The base replaces your halogen and nothing else happens.
 Step one: Strong nucleophile adds to the ring, generating carbanion
intermediate
NO2 NO2
Br -OH Br
OH
NO2 - NO
2
NO2 NO2
 Step two: Leaving group leaves, regenerating aromaticity.
NO2 NO2
Br OH
OH
-
NO2 NO2
NO2 NO2
o Elimination-Addition (Benzyne)
 Overall reaction: Halogen leaves and strong base goes where the halogen
was or one away in either direction.
 Recognizing that this is the reaction you’re doing
• Halogen on the ring
• Megabase (most likely NH2-)
• Most likely something else on the ring acting as a place-holder.
 Step one: Base and substrate undergo E2-like reaction.

H -
NH2

Cl
benzyne
• This really happens in two steps, not 1.
  Step two: Base attacks benzyne intermediate and proton is picked up at
other side of triple bond.

-NH
2
NH2

H+ H

Halogen’s relationship to other substituent Possible products

Ortho Ortho, Meta

Meta Ortho, Meta, Para

Para Meta, Para

• A weird reaction of phenols!

O O
OH
O COO_
_
_ OH

H+
OH
O
COOH
COOH