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
