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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

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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

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16.2 Reactions of Substituents on Benzene

A. Reactions of Alkyl Substituents

NBS

peroxide

or hν

Br

OH

CN

tert-BuO

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H2, Pt

N

O

H2, Pt

H2, Pt

B. Oxidations of Alkyl Substituents

1. KMnO4, heat (reflux)

2. H+

Na2Cr2O7, H+, heat

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Na2Cr2O7, H+, heat

Na2Cr2O7, H+, heat

Na2Cr2O7, H+, heat

OHMnO2

(no heating needed)

OH

Na2Cr2O7, H+, heat

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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)

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A. Relative rate of electrophilic aromatic substitution

Examples:

OCH3 NO2

• Rate-determining step (r.d.s)

• Resonance effect and inductive effect

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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

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Weak activating groups (substituents)

R

Weak deactivating groups (substituents)

F Cl Br I

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Moderate deactivating groups (substituents)

O H O R O OR OHN

R

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Strong deactivating groups (substituents)

SO3H NO2 CN NR3

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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

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(iii)

Br

Cl2, FeCl3

(iv)

ORBr2 (1 equivalent)

FeCl3

ORBr2 (excess)

FeCl3

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(v)

NH2

HN

O

R

CH3COClAlCl3

CH3COClAlCl3

(vi)

O R

NO2

HNO3

H2SO4

HNO3

H2SO4

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(vii) Synthesis of trinitrotoluene

CH3

HNO3

H2SO4

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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

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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

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A. Examples

(i)

from

OH

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(ii)

from

CH3O

O2N

(iii)

from

CH3

NO2

O

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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:

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B. Reaction of arenediazonium salt with nucleophiles

Sandmeyer reation (CuBr, CuCl, and CuCN)

Reaction with KI, HBF4, H3O+, and H3PO2

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16.11 The Arenediazonium Ion as an Electrophile

N

N

Nu

* Nucleophile better be bulky

* Terminal nitrogen reacts with nucleophile

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16.13 Nucleophilic Aromatic Substitution (SNAr) Reactions

A. Comparison of SNAr, SN1, and SN2

B. General mechanism

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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

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16.14 Benzyne