Chapter 16 Study Slides

Electrophilic Aromatic Substitution
• We will discuss five reactions

– Halogenation (adding a halogen)
– Nitration (adding –NO2)
– Sulfonation (adding –SO3H)
– Alkylation (adding –R group)
– Acylation (adding –COR group)
2
Halogenation
• Reaction
Halogen can be Cl2 or Br2
Catalyst can be FeCl3,
FeBr3 or AlCl3
• Mechanism
3
Halogenation
• Summary
4
Nitration
• Reaction
• Mechanism
5
Nitration
• If you want to make aniline…
6
Sulfonation
• Reaction
• Mechanism
7
Friedel-Crafts Alkylation
• Reaction
• Mechanism
• Watch out for carbocation rearrangements!!!

8
Friedel-Crafts Acylation
• Reaction
• Mechanism
Requires a
water workup
9
Preparing Acid Chlorides
• Using thionyl chloride
• Using phosphorus pentachloride
10
Limitations of Friedel-Crafts Reactions
• Carbocations can rearrange
1° carbocation 2° carbocation
is not favored is more stable
• Electron withdrawing groups (EWGs) give poor yields
The ring acts a EWGs make

nucleophile & the ring less
needs to be negative
negative 11
Limitations of Friedel-Crafts Reactions
• Aryl & vinyl halides cannot be used because
they do not form carbocations readily
• Polyalkylation often occurs
Alkyl groups activate the ring allowing

multiple alkylations to occur This does not happen with acylation 12
Substituent Effects
• Substituents affect the reactivity of an
aromatic ring
• They also affect the orientation of the reaction
• Examples:
• Nitro group is an electron • Hydroxyl group is an electron

withdrawing group (EWG) donating group (EDG)
• It deactivates the ring • It activates the ring
• It is a meta director • It is an ortho/para director
13
Substituent Effects
• Activating groups
– Electron donating groups
– They make the ring more negative (nucleophilic) and more
reactive
– Direct the next group to the ortho or para position
– Examples:
-OH -NH2 -CH3 -OCH3
-Ph -NHCOCH3 -OCOCH3 -OR
14
Substituent Effects
• Deactivating groups
– Electron withdrawing groups
– They make the ring less negative and less reactive
– Direct the next group to the meta position
– Examples:
-NO2 -CN -SO3H
-COR -COOH -CHO
15
Substituent Effects
• In general
– If the atom next to the ring has a lone pair(s) it
usually activates the ring
– If the atom next to the ring is double bonded to an
electronegative atom, it usually deactivates the
ring
• Exceptions: Halogens
– They are ortho/para directors
– They deactivate the ring
16
Substituent Effects
• Why do groups activate or deactivate and
direct ortho/para or meta…
• … it has to do with resonance or inductive
effects
• Some groups push electrons into the ring
while other pull electrons out of the ring
An –OH group activates A –CF3 group deactivates

the ring via resonance 17
the ring via inductive effects
Resonance Effects
• Adding an extra resonance structure can increase
stability
• Electron donating: −NH2, −NR2, −OH, −OR
• Electron withdrawing: −CHO, −COOH, −CN, −NO2
EDGs increase negative EWGs increase positive

charge on the ortho & para charge on the ortho & para
sites; this is why they sites; this is why they
typically direct ortho/para typically direct meta because
the most negative location is 18
the meta site
Nucleophilic Aromatic Substitution
• Why can’t aryl or vinyl halides do SN2?
• It requires backside attack
24
• Nucleophilic substitutions can occur under certain conditions
25
• Mechanism
27
• The resonance structures shown in the
mechanism are called the Meisenheimer
intermediate
• The carboanion is stabilized by the electron
withdrawing groups
28
Benzyne Elimination-Addition
• NH2– (amide) is a very strong base

• The reaction is done in liquid ammonia
• It involves a highly unstable intermediate
(benzyne)
29
Benzyne Elimination-Addition
• Mechanism
30
Side Chains
• Common compounds with aliphatic side chains
• Benzylic radicals & cations
Both are resonance stabilized
32
Bromination of Side Chains
• To brominate the benzylic position, use NBS
• Why it brominates there? → Radical stability
33
Conjugated Side Chains
• Conjugated systems are more stable than those that
are not conjugated
• HBr & peroxide
• HBr & no peroxide
34
Reduction of Side Chains
• Clemmenson reduction (acidic conditions)
• Wolff-Kishner reduction (basic conditions)
35
Oxidation of Side Chains
• The alkyl side chains of an aromatic ring can be
oxidized by KMnO4 if it has a benzylic hydrogen(s)
36
Protecting/Blocking Groups
• Aniline (amine) → Acetanilide (amide)
• Acetanilide will direct the next group para only
To remove
acetyl group
37
Protecting/Blocking Groups
• Sulfonic acids can be used to block certain
sites on the ring
38
To remove acetyl group To remove sulfonic acid
Disubstituted Benzenes
• The two groups select the orientation of a 3rd
group
The stronger activating

group determined the
outcome of the reaction
39
Reduction of Benzene
• Ni catalyst and hydrogen gas can completely
reduce benzene to a cycloalkane
• Sodium metal can reduce benzene to a diene
41
Organic Synthesis
• Practice #1
• Propose a synthetic route the following compound
43
Organic Synthesis
• Practice #2
• Propose a synthetic route the following compound
45
Organic Synthesis
• Practice #3
• Identify the reagents needed for each step of the following
synthesis
47

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Electrophilic Aromatic Substitution

• We will discuss five reactions

• Watch out for carbocation rearrangements!!!

• Using phosphorus pentachloride

The ring acts a EWGs make

• Polyalkylation often occurs

Alkyl groups activate the ring allowing

• Nitro group is an electron • Hydroxyl group is an electron

An –OH group activates A –CF3 group deactivates

EDGs increase negative EWGs increase positive

• It requires backside attack

• NH2– (amide) is a very strong base

• Benzylic radicals & cations

Both are resonance stabilized

• Why it brominates there? → Radical stability

• HBr & no peroxide

• Wolff-Kishner reduction (basic conditions)

• Acetanilide will direct the next group para only

The stronger activating

• Sodium metal can reduce benzene to a diene

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