Download Electron-donating substituents increase the rate of substitution

Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 16
Reactions
of
Substituted
Benzenes
1
© 2011 Pearson Education, Inc.
Examples of Substituted Benzenes
2
© 2011 Pearson Education, Inc.
Nomenclature of Substituted Benzenes
In disubstituted benzenes, the relative positions of the
two substituents are indicated by numbers or by prefixes:
3
© 2011 Pearson Education, Inc.
The two substituents are listed in alphabetical order:
4
© 2011 Pearson Education, Inc.
• 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
© 2011 Pearson Education, Inc.
Some disubstituted benzenes have common names that
incorporate both substituents:
6
© 2011 Pearson Education, Inc.
Naming Polysubstituted Benzenes
The substituents are numbered in the direction that
results in the lowest possible number:
7
© 2011 Pearson Education, Inc.
The substituent incorporated into the common name is
the 1-position:
Always give substituents the lowest possible numbers!
8
© 2011 Pearson Education, Inc.
Substituted benzenes undergo the five electrophilic
aromatic substitution reactions discussed in Chapter 15:
9
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
Inductive Electron Withdrawal
Electron Donation by Hyperconjugation
11
© 2011 Pearson Education, Inc.
Resonance Electron Donation and Withdrawal
Substituents such as NH2, OH, OR, and Cl donate
electrons by resonance, but they also withdraw electrons
inductively:
12
© 2011 Pearson Education, Inc.
Substituents such as C=O, CΞN, SO3H, and NO2
withdraw electrons by resonance:
13
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
Electron-Donating Substituents
Electron donation into the benzene ring by resonance is
more significant than inductive electron withdrawal from
the ring:
15
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
These substituents are less effective in donating
electrons into the ring because…
17
© 2011 Pearson Education, Inc.
Alkyl, aryl, and CH=CHR groups are weakly activating
substituents because they are slightly more electron
donating than they are electron withdrawing:
18
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
These substituents withdraw electrons both inductively
and by resonance:
20
© 2011 Pearson Education, Inc.
These substituents are powerful electron-withdrawing
groups:
Except for the ammonium ions, these substituents
withdraw electrons both inductively and by resonance
21
© 2011 Pearson Education, Inc.
The substituent already attached to the benzene ring
determines the location of the new substituent:
22
© 2011 Pearson Education, Inc.
All activating substituents are ortho–para directors:
23
© 2011 Pearson Education, Inc.
The weakly deactivating halogens are ortho–para
directors:
24
© 2011 Pearson Education, Inc.
All substituents that are more deactivating than halogens
are meta directors:
25
© 2011 Pearson Education, Inc.
An ortho,para-directing substituent:
26
© 2011 Pearson Education, Inc.
An ortho,para-directing substituent:
27
© 2011 Pearson Education, Inc.
An meta-directing substituent:
28
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
32
The ortho–para product ratio decreases with an increase
in the size of the substituents:
33
© 2011 Pearson Education, Inc.
34
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
A benzene ring with a meta director cannot undergo a
Friedel–Crafts reaction:
36
© 2011 Pearson Education, Inc.
Aniline and N-substituted anilines do not undergo
Friedel–Crafts reaction:
Phenol and anisole undergo Friedel–Crafts reactions at
the ortho and para positions
Aniline cannot be nitrated, because it is oxidized by nitric
acid
37
© 2011 Pearson Education, Inc.
In designing a disubstituted benzene, consider
the order of substitution:
38
© 2011 Pearson Education, Inc.
The Friedel–Crafts acylation must be carried out first,
because the nitro group is strongly deactivating:
39
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
To synthesize p-propylbenzenesulfonic acid:
• Introduce the propyl group by Friedel–Crafts
acylation followed by reduction.
• Sulfonation of the propylbenzene product affords
the para derivative.
How is the meta derivative prepared?
• Friedel–Crafts acylation
• Sulfonation
• Carbonyl reduction
41
© 2011 Pearson Education, Inc.
Synthesis of Trisubstituted Benzenes
42
© 2011 Pearson Education, Inc.
Steric hindrance makes the position between the
substituents less accessible
43
© 2011 Pearson Education, Inc.
A strongly activating substituent will win out over a
weakly activating substituent or a deactivating
substituent
44
© 2011 Pearson Education, Inc.
If the two substituents have similar activating properties,
neither will dominate:
45
© 2011 Pearson Education, Inc.
Synthesis of Substituted Benzenes
Using Arenediazonium Salts
46
© 2011 Pearson Education, Inc.
Preparation of the Diazonium Salt
Mechanism:
Nitrosonium ion formation
47
© 2011 Pearson Education, Inc.
Diazonium ion formation:
Caution: Diazonium salts are explosive!
48
© 2011 Pearson Education, Inc.
The reaction stops because a secondary amine lacks a
second proton:
49
© 2011 Pearson Education, Inc.
The bulky dialkyl amino group blocks the approach of the
nitrosonium ion to the ortho position:
[unnumbered fig, pg 690]
50
© 2011 Pearson Education, Inc.
51
© 2011 Pearson Education, Inc.
Consider the synthesis of para-chloroethylbenzene:
52
© 2011 Pearson Education, Inc.
Fluorination and Iodination of Benzene
53
© 2011 Pearson Education, Inc.
Hydroxylation of Benzene
54
© 2011 Pearson Education, Inc.
Summary of Diazonium Reactions
55
© 2011 Pearson Education, Inc.
Synthesis Example
Propose a
synthesis from a
monosubstituted
benzene
Synthetic target:
Answer:
56
© 2011 Pearson Education, Inc.
The Arenediazonium Ion as an
Electrophile
Only highly activated benzene rings can undergo this
reaction
Substitution takes place preferentially at the para
position
57
© 2011 Pearson Education, Inc.
However, if the para position is blocked …
58
© 2011 Pearson Education, Inc.
Mechanism:
59
© 2011 Pearson Education, Inc.
Diazo Dyes
Diazonium coupling affords synthetic dyes:
Large dipole results in deep color (high extinction
coefficient):
Electronic “push-pull”
produces a dipole
60
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
Nucleophilic Aromatic Substitution
Reactions
Nucleophilic aromatic substitution reactions require at least one
strongly electron-withdrawing substituent to occur:
62
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
64
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
The incoming group has to be a stronger base than the
group that is being replaced:
66
© 2011 Pearson Education, Inc.
Agent Orange and Nucleophilic
Aromatic Substitution
Synthesis of Agent Orange:
Side reaction:
Dioxin is carcinogenic and causes birth defects
67
© 2011 Pearson Education, Inc.
Formation of Benzyne
68
© 2011 Pearson Education, Inc.
69
© 2011 Pearson Education, Inc.
70
© 2011 Pearson Education, Inc.
Benzyne Is an Extremely Reactive
Species
71
© 2011 Pearson Education, Inc.
Polycyclic Benzoid Hydrocarbons
72
© 2011 Pearson Education, Inc.