Reactions of Substituted Benzenes: 6 Edition Paula Yurkanis Bruice

Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 16
Reactions
of
Substituted
Benzenes
1
2011 Pearson Education, Inc.
Examples of Substituted Benzenes
2
Nomenclature of Substituted Benzenes

In disubstituted benzenes, the relative positions of the
two substituents are indicated by numbers or by prefixes:
3
The two substituents are listed in alphabetical order:
4
Common names are preferred in naming certain

substituted benzenes, e.g., toluene, aniline, phenol.
Do not deconstruct the common name; e.g., do not
change toluene to methylbenzene.
The substituent that is part of the common name is
position 1, but do not label as such in the chemical name.
5
Some disubstituted benzenes have common names that

incorporate both substituents:
6
Naming Polysubstituted Benzenes

The substituents are numbered in the direction that
results in the lowest possible number:
7
The substituent incorporated into the common name is

the 1-position:
Always give substituents the lowest possible numbers!
8
Substituted benzenes undergo the five electrophilic

aromatic substitution reactions discussed in Chapter 15:
9
The slow step of an electrophilic aromatic substitution

reaction is the formation of the carbocation intermediate:
Electron-donating substituents increase the rate of
substitution reactions by stabilizing the carbocation
intermediate.
Electron-withdrawing substituents decrease the rate of
substitution reactions by destabilizing the carbocation
intermediate.
10
Inductive Electron Withdrawal
Electron Donation by Hyperconjugation
11
Resonance Electron Donation and Withdrawal

Substituents such as NH2, OH, OR, and Cl donate
electrons by resonance, but they also withdraw electrons
inductively:
12
Substituents such as C=O, CN, SO3H, and NO2

withdraw electrons by resonance:
13
Electron-donating substituents
increase the reactivity of
the benzene ring toward
electrophilic aromatic substitution
Electron-withdrawing substituents
decrease the reactivity of the
benzene ring toward electrophilic
aromatic substitution
14
Electron-Donating Substituents
Electron donation into the benzene ring by resonance is
more significant than inductive electron withdrawal from
the ring:
15
Resonance donation into the benzene ring competes

with resonance donation into the carbonyl
Inductive withdrawal into the benzene ring also occurs
Overall, these substituents weakly release electrons
16
These substituents are less effective in donating

electrons into the ring because
17
Alkyl, aryl, and CH=CHR groups are weakly activating

substituents because they are slightly more electron
donating than they are electron withdrawing:
18
These substituents donate into the ring by resonance

and withdraw electrons from the ring inductively:
They withdraw electrons inductively more strongly than

they donate electrons by resonance
19
These substituents withdraw electrons both inductively

and by resonance:
20
These substituents are powerful electron-withdrawing

groups:
Except for the ammonium ions, these substituents

withdraw electrons both inductively and by resonance
21
The substituent already attached to the benzene ring

determines the location of the new substituent:
22
All activating substituents are orthopara directors:
23
The weakly deactivating halogens are orthopara

directors:
24
All substituents that are more deactivating than halogens

are meta directors:
25
An ortho,para-directing substituent:
26
An ortho,para-directing substituent:
27
An meta-directing substituent:
28
The Effect of Substituents on pKa

Electron-withdrawing groups stabilize a base and
therefore increase the strength of its conjugate acid
Electron-donating groups destabilize a base and thus
decrease the strength of its conjugate acid
29
The more electronic deficient a substituent on phenol,

the stronger the acid:
To understand the relative pKa values, consider the delocalization of

the phenolate anion (stars show anion distribution):
Unstable
More stable anion =

lower pKa
Stable: through resonance

of anion into nitro
30
The more electronic deficient a substituent on benzoic

acid, the stronger the acid:
Substituent effect on pKa is minimal in benzoic acids

because only inductive electronic effects are present:
Why?
Because the benzene ring is
cross conjugated with the
carboxylate anion
31
The more electronic deficient a substituent on a

protonated aniline, the stronger the acid:
To understand the relative pKa values, consider the delocalization of the

aniline lone pair of the conjugate base (stars show anion distribution):
Unstable
More stable lone pair
= lower pKa
Stable: through resonance

of lone pair into nitro
32
The orthopara product ratio decreases with an increase

in the size of the substituents:
33
34
Methoxy and hydroxy substituents are so strongly

activating that halogenation is carried out without a
Lewis acid:
The presence of Lewis acid and excess bromine

generates the tribromo derivative:
35
A benzene ring with a meta director cannot undergo a

FriedelCrafts reaction:
36
Aniline and N-substituted anilines do not undergo

FriedelCrafts reaction:
Phenol and anisole undergo FriedelCrafts reactions at

the ortho and para positions
Aniline cannot be nitrated, because it is oxidized by nitric
acid
37
In designing a disubstituted benzene, consider

the order of substitution:
38
The FriedelCrafts acylation must be carried out first,

because the nitro group is strongly deactivating:
39
In the synthesis of para-chlorobenzoic acid from toluene,

the methyl group is oxidized after chlorination:
In the synthesis of meta-chlorobenzoic acid, the methyl

group is oxidized before chlorination:
40
To synthesize p-propylbenzenesulfonic acid:

Introduce the propyl group by FriedelCrafts
acylation followed by reduction.
Sulfonation of the propylbenzene product affords
the para derivative.
How is the meta derivative prepared?

FriedelCrafts acylation
Sulfonation
Carbonyl reduction
41
Synthesis of Trisubstituted Benzenes
42
Steric hindrance makes the position between the

substituents less accessible
43
A strongly activating substituent will win out over a

weakly activating substituent or a deactivating
substituent
44
If the two substituents have similar activating properties,

neither will dominate:
45
Synthesis of Substituted Benzenes

Using Arenediazonium Salts
46
Preparation of the Diazonium Salt
Mechanism:
Nitrosonium ion formation
47
Diazonium ion formation:
Caution: Diazonium salts are explosive!

48
The reaction stops because a secondary amine lacks a

second proton:
49
The bulky dialkyl amino group blocks the approach of the

nitrosonium ion to the ortho position:
[unnumbered fig, pg 690]
50
51
Consider the synthesis of para-chloroethylbenzene:
52
Fluorination and Iodination of Benzene
53
Hydroxylation of Benzene
54
Summary of Diazonium Reactions
55
Synthesis Example
Propose a
synthesis from a
monosubstituted
benzene
Synthetic target:
Answer:
56
The Arenediazonium Ion as an

Electrophile
Only highly activated benzene rings can undergo this

reaction
Substitution takes place preferentially at the para
position
57
However, if the para position is blocked
58
Mechanism:
59
Diazo Dyes
Diazonium coupling affords synthetic dyes:
Large dipole results in deep color (high extinction

coefficient):
Electronic push-pull
produces a dipole
60
Diazo Dyes and Sulfa Drugs

Gerhard Domagk studied the antibiotic properties of diazo
dyes. He was awarded the Nobel Prize for medicine in 1939
for his work.
Domagk cured his

daughter of strep
with sulfanilamide
The dye prontosil is

reduced to the sulfa
drug sulfanilamide
Sulfanilamide looks like PABA, a bacterial nutrient:
61
Nucleophilic Aromatic Substitution

Reactions
Nucleophilic aromatic substitution reactions require at least one
strongly electron-withdrawing substituent to occur:
62
Electron-withdrawing substituents increase the reactivity

of the benzene ring toward nucleophilic substitution and
decrease the reactivity of the benzene ring toward
electrophilic substitution
63
64
The electron-withdrawing substituents must be ortho or

para to the site of nucleophile attack,
so that electrons of the attacking nucleophile can be

delocalized into these substituents
65
The incoming group has to be a stronger base than the

group that is being replaced:
66
Agent Orange and Nucleophilic

Aromatic Substitution
Synthesis of Agent Orange:
Side reaction:
Dioxin is carcinogenic and causes birth defects

67
Formation of Benzyne
68
69
70
Benzyne Is an Extremely Reactive

Species
71
Polycyclic Benzoid Hydrocarbons
72

Reactions of Substituted Benzenes: 6 Edition Paula Yurkanis Bruice

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Organic Chemistry

Examples of Substituted Benzenes

Nomenclature of Substituted Benzenes

The two substituents are listed in alphabetical order:

Common names are preferred in naming certain

Some disubstituted benzenes have common names that

Naming Polysubstituted Benzenes

The substituent incorporated into the common name is

Always give substituents the lowest possible numbers!

Substituted benzenes undergo the five electrophilic

The slow step of an electrophilic aromatic substitution

Inductive Electron Withdrawal

Electron Donation by Hyperconjugation

Resonance Electron Donation and Withdrawal

Substituents such as C=O, CN, SO3H, and NO2

Resonance donation into the benzene ring competes

These substituents are less effective in donating

Alkyl, aryl, and CH=CHR groups are weakly activating

These substituents donate into the ring by resonance

They withdraw electrons inductively more strongly than

These substituents withdraw electrons both inductively

These substituents are powerful electron-withdrawing

Except for the ammonium ions, these substituents

The substituent already attached to the benzene ring

All activating substituents are orthopara directors:

The weakly deactivating halogens are orthopara

All substituents that are more deactivating than halogens

The Effect of Substituents on pKa

The more electronic deficient a substituent on phenol,

To understand the relative pKa values, consider the delocalization of

More stable anion =

Stable: through resonance

The more electronic deficient a substituent on benzoic

Substituent effect on pKa is minimal in benzoic acids

The more electronic deficient a substituent on a

To understand the relative pKa values, consider the delocalization of the

Stable: through resonance

The orthopara product ratio decreases with an increase

Methoxy and hydroxy substituents are so strongly

The presence of Lewis acid and excess bromine

A benzene ring with a meta director cannot undergo a

Aniline and N-substituted anilines do not undergo

Phenol and anisole undergo FriedelCrafts reactions at

In designing a disubstituted benzene, consider

The FriedelCrafts acylation must be carried out first,

In the synthesis of para-chlorobenzoic acid from toluene,

In the synthesis of meta-chlorobenzoic acid, the methyl

To synthesize p-propylbenzenesulfonic acid:

How is the meta derivative prepared?

Synthesis of Trisubstituted Benzenes

Steric hindrance makes the position between the

A strongly activating substituent will win out over a

If the two substituents have similar activating properties,

Synthesis of Substituted Benzenes

Preparation of the Diazonium Salt

Diazonium ion formation:

Caution: Diazonium salts are explosive!

The reaction stops because a secondary amine lacks a

The bulky dialkyl amino group blocks the approach of the

[unnumbered fig, pg 690]

Consider the synthesis of para-chloroethylbenzene:

Fluorination and Iodination of Benzene

Summary of Diazonium Reactions