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1
Chapter 16: Reactions of Substituted Benzenes
Learning Objectives:
1. Be able to recognize and utilize the oxidative and reductive reactions involving the
substituents on benzene.
2. Recognize whether a substituent on a benzene ring is activating or deactivating
toward electrophilic aromatic substitution reaction, and why it is so.
3. Predict the effect a substituent will have on the regioselectivity of an electrophilic
substitution reaction.
4. Predict the effect a substituent will have on pKa.
5. Be able to design the synthesis of a multisubstituted benzene.
6. Be able to recognize and utilize the reactions involving arenediazonium salts.
7. Recognize and be able to write the mechanism of nucleophilic aromatic substitution.
8. Recognize the structure of benzyne, be able to explain how it is formed, and how it
reacts.
Sections:
16.1 Nomenclature of Disubstituted and Polysubstituted Benzenes
16.2 Reactions of Substituents on Benzene
16.3 The Effect of Substituents on Reactivity*
16.4 The Effect of Substituents on Orientation (Regioselectivity)*
16.5 The Effect Substituent on pKa
16.6 The Ortho-para ratio
16.7 Additional Considerations Regarding Substituent Effects
16.8 Designing a Synthesis III: Synthesis of monosubstituted and Disubstituted
Benzenes*
16.9 Synthesis of Trisubstituted Benzenes
16.10 Synthesis of Substituted Benzenes Using Arenediazonium Salts*
16.11 The Arenediazonium Ion as an Electrophile*
16.12 Mechanism for the Reaction of Amines with Nitrous Acid*
16.13 Nucleophilic Aromatic Substitution Reactions*
16.14 Benzyne
16.15 Polycyclic Benzenoid Hydrocarbons#
16.16 Electrophilic Substitution Reactions of Naphthalene and Substituted
Naphthalene#
* Sections that will be focused # Sections that will be skipped
Recommended additional problems
16.36 – 6.41, 6.43 – 6.55, 6.57 – 6.60, 6.62 – 6.68
2
Class Note
16.1 Nomenclature of Disubstituted and Polysubstituted Benzenes
Br
Br
Br
NO2NO2
H2N
Br
OH
NO2
Br
Cl
Br
NO2
Cl
CH3
Br
Cl
Br
NH2
Cl
Br
CH3
3
16.2 Reactions of Substituents on Benzene
A. Reactions of Alkyl Substituents
NBS
peroxide
or hν
Br
OH
CN
tert-BuO
4
H2, Pt
N
O
H2, Pt
H2, Pt
B. Oxidations of Alkyl Substituents
1. KMnO4, heat (reflux)
2. H+
Na2Cr2O7, H+, heat
5
Na2Cr2O7, H+, heat
Na2Cr2O7, H+, heat
Na2Cr2O7, H+, heat
OHMnO2
(no heating needed)
OH
Na2Cr2O7, H+, heat
6
C. Reduction of Nitro Group
H2, PtNO2
NO2 Sn, HCl
NO2 Fe, HCl
16.3 The Effect of Substituents on Reactivity and 16.4 The Effect of Substituents
on Orientation (Regioselectivity)
EDG EWG
electron donation group (EDG)
electron withdrawing group (EWG)
7
A. Relative rate of electrophilic aromatic substitution
Examples:
OCH3 NO2
• Rate-determining step (r.d.s)
• Resonance effect and inductive effect
8
B. Relative reactivity and regioselectivity of substituted benzenes
Strong activating groups (substituents)
NH2 OH OR
Moderate activating groups (substituents)
HN O
O
R
O
R
9
Weak activating groups (substituents)
R
Weak deactivating groups (substituents)
F Cl Br I
10
Moderate deactivating groups (substituents)
O H O R O OR OHN
R
11
Strong deactivating groups (substituents)
SO3H NO2 CN NR3
12
C. Examples (combined with 16.6 The Ortho-para ratio and 16.7 Additional
Considerations Regarding Substituent Effects)
(i)
CH3
Br2, FeCl3
(ii)
CH3 HNO3
H2SO4
CH2CH3 HNO3
H2SO4
C(CH3)3 HNO3
H2SO4
13
(iii)
Br
Cl2, FeCl3
(iv)
ORBr2 (1 equivalent)
FeCl3
ORBr2 (excess)
FeCl3
14
(v)
NH2
HN
O
R
CH3COClAlCl3
CH3COClAlCl3
(vi)
O R
NO2
HNO3
H2SO4
HNO3
H2SO4
15
(vii) Synthesis of trinitrotoluene
CH3
HNO3
H2SO4
16
16.5 The Effect Substituent on pKa
OHOH
CH3
OH
OCH3
OH
CHO
OH
Cl
OH
NO2
I II III IV V VI
CO2HCO2H
CH3
CO2H
OCH3
CO2H
CHO
CO2H
Br
CO2H
NO2
I II III IV V VI
NH3NH3
CH3
NH3
OCH3
NH3
CHO
NH3
Br
NH3
NO2
I IIIII
IV V VI
17
16.8 Designing a Synthesis III: Synthesis of monosubstituted and Disubstituted
Benzenes and 16.9 Synthesis of Trisubstituted Benzenes
Design multiple-step synthesis:
* Selectivity: chemoselectivity, regioselectivity, and stereoselectivity
* Retrosynthetic analysis: breaking and formation of chemical bonds
18
A. Examples
(i)
from
OH
19
(ii)
from
CH3O
O2N
(iii)
from
CH3
NO2
O
20
16.12 Mechanism for the Reaction of Amines with Nitrous Acid and 16.10 Synthesis
of Substituted Benzenes Using Arenediazonium Salts
A. Formation of diazonium salt
R NH2
NaNO2, HCl
0oCR N N Cl
diazonium salt
Mechanism:
21
B. Reaction of arenediazonium salt with nucleophiles
Sandmeyer reation (CuBr, CuCl, and CuCN)
Reaction with KI, HBF4, H3O+, and H3PO2
22
16.11 The Arenediazonium Ion as an Electrophile
N
N
Nu
* Nucleophile better be bulky
* Terminal nitrogen reacts with nucleophile
23
16.13 Nucleophilic Aromatic Substitution (SNAr) Reactions
A. Comparison of SNAr, SN1, and SN2
B. General mechanism
24
C. Examples
(i)
Cl
NO2
Cl
NO2
Cl
NO2
NO2
NO2O2N
OH
OH
OH
OH
NO2
OH
NO2
OH
NO2
NO2
NO2O2N
(ii)
Br
NO2
NO2
NHCH2CH3
NO2
NO2CH3CH2NH2
then OH
25
16.14 Benzyne