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 resonancestabilized carbocation intermediate (sigma complex)
E+
E
E
E
This is the slow step because it breaks up the aromaticity.

Loss of a proton restores aromaticity
E
E
o Nitration
 Generation of the nitronium ion
H2SO4
nitronium ion
 Electrophilic attack
 Loss of proton
o Sulfonation
H2SO4

SO3 is also a powerful electrophile, but less so.
 This reaction is reversible – Steam it!
o Halogenation
 Bromination
 Bromine reacts with FeBr3 to form the electrophile

Electrophilic attack

Loss of proton

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
_
AlCl3
Cl-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.

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
_
AlCl3
AlCl3


 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
RBr/FeBr3
“R+”
R
Acylation
Acid chloride/ AlCl3 Acyllium ion
R
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.



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.

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 Multiple substituents
 When possible, make everyone happy.
o-, p-director
Cl2, AlCl3
m-director

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
Carbonyls
alkyl groups
-CN
-NH2
most activating
least activating

-OR
Side-chain reactions
o Clemmenson Reduction
 Chops off the carbonyl of ketones
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.
KMnO4

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
AlCl3

Step 2: Put the other piece on
HNO3
H2SO4

Step 3: Oxidize
O2 N
COOH
KMnO4
O2 N
O2 N

Two ortho-, para-directors meta to each other
?

Step 1: Acylate
AlCl3

Step 2: Put the other piece on
I2
HNO3

Step 3: Reduce
Zn(Hg)
HCl (aq)


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
-
OH
NO2
NO2

OH
- NO
2
NO2
Step two: Leaving group leaves, regenerating aromaticity.
NO2
NO2
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.
-NH
2
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.
-
NH2
NH2
H+
Halogen’s relationship to other substituent
Possible products
Ortho
Ortho, Meta
Meta
Ortho, Meta, Para
Para
Meta, Para

A weird reaction of phenols!
OH
_
COO_
_
OH
H+
OH
COOH
COOH