Chapter 12 - Reactions of Benzene - EAS

12.1 Introduction to benzene vs. alkenes 12.2 Mechanistic principles of Electrophilic Aromatic Subsitution 12.3 Nitration of benzene, reduction to aminobenzenes 12.4 Sulfonation of benzene 12.5 Halogenation of benzene 12.6 Friedel-Crafts alkylation of benzene 12.7 Friedel-Crafts alkylation of benzene 12.8 Alkylbenzenes via acylation then reduction 12.9 Rate and regioselectivity in EAS 12.10 Nitration of toluene - rate and regioselectivity

12.11 Nitration of CF3-benzene - rate and regioselectivity 12.12 Substituent effects in EAS: Activating Substituents 12.13 Substituent effects in EAS: Strongly Deactivating Substituents 12.14 Substituent effects in EAS: Halogens 12.15 Multiple substituent effects in EAS 12.16 Regioselective synthesis of disubstituted aromatic compounds 12.17 Substitution in Naphthalene 12.18 Substitution in heterocyclic aromatic compounds

1 Introduction – Benzene vs. Alkenes

Br Br Br

no heat Br dark

Br Br no colour change no heat (no reaction) dark

Completely delocalized (6) pi system lends stability (aromatic)

12.2 Mechanistic Principles of EAS

Alkenes react by addition

E Y E E

Y Y

Benzene reacts by substitution

Y E Y H E E - H Y

Resonance-stabilized cation

2 General Mechanism of EAS on Benzene

Energy diagram for EAS in benzene Figure 12.1

Electrophilic Aromatic Substitutions on Benzene

H NO HNO3, H2SO4 2 12.3 Nitration

H SO , H SO SO3H 12.4 Sulfonation 3 2 4

H Br , Fe Br 12.5 Halogenation 2

3 12.6 Friedel-Crafts Alkylation of Benzene

H CH2CH3 CH3CH2Cl

AlCl3

CH3

H C CH3 (CH3)3CCl CH3 AlCl3

H3C CH Cl 3 H C CH3 CH3 CH3 AlCl3

Problems: Alkyl groups may rearrange during reaction Products are more reactive than benzene

Uses: Alkyl benzenes readily oxidized to benzoic acids using KMnO4

12.7 Friedel-Crafts Acylation of Benzene

O O H C RCCl R

AlCl3

O O O H CCH3 H3C O CH3

AlCl3

O AlCl3 O RCCl RC RCO

Products react more slowly than benzene - cleaner reaction No carbocation rearrangements

4 12.8 Alkylbenzenes via Acylation/Reduction

O Zn, HCl H H C (Clemmensen) C R R

NH2NH2, KOH heat (Wolff-Kischner)

Cl AlCl3 Zn, HCl

Make the acyl benzene first (clean, high yielding reaction)

Reduce the ketone group down to the methylene (C=O to CH2) Avoids rearrangement problems, better yields

Aminobenzenes via Nitration/Reduction (not in text)

O H Sn, HCl N N O H

H H HNO , H SO NO2 Sn, HCl N 3 2 4 H

Make the nitro benzene first, clean high yielding reaction Reduce the nitro group down to the amine Difficult to introduce the amino group by other methods

5 12.9 Activation and Deactivation by Substituents (Rates)

X X

HNO3, H2SO4 NO2

CF3 H CH3

0.000025 1.0 25

Relative rates in nitration reaction now bringing in a second substituent

12.9 Nitration of Toluene vs Nitration of (Trifluoromethyl)benzene

CH3 CH3 CH3 CH3 HNO3, H2SO4 NO2 ++

NO2

63%3%34%

CH3 is said to be an ortho/para director (o/p director) - Regioselectivity

CF3 CF3 CF3 CF3 HNO3, H2SO4 NO2 ++

NO2

6% 91% 3%

CF3 is said to be a meta director (m director) - Regioselectivity

6 12.10 Rate and Regioselectivity in Nitration of Toluene

CH3 CH3 CH3 CH3 HNO3, H2SO4 NO2 ++

NO2

63% 3% 34%

Fig. 12.5 – Energy diagrams for toluene nitration (vs. benzene)

12.11 Rate and Regioselectivity in Nitration of CF3C6H5

CF3 CF3 CF3 CF3 HNO3, H2SO4 NO2 ++

NO2

6% 91% 3%

Fig. 12.6 – Energy diagrams for CF3C6H5 nitration (vs. benzene)

7 12.12 Substituent Effects – Activating Substituents

General : all activating groups are o/p directors halogens are slightly deactivating but are o/p directors strongly deactivating groups are m directors

Activating Substituents

O R HO RO RCO

alkyl hydroxyl alkoxy acyloxy

OCH3 OCH3 OCH3 HNO3, H2SO4 Example: NO2 +

NO2

Alkyl groups stabilize carbocation by hyperconjugation Lone pairs on O (and others like N) stabilize by resonance

12.13 Subst. Effects – Strongly Deactivating Substituents

O O O O O HC R C HO C Cl C RO C

aldehyde ketone carboxylic acid acyl chloride ester

N C HO S O2N O nitrile sulfonic acid nitro

NO2 NO2 Br2, Fe Example:

Second substituent goes meta by default – best carbocation

8 12.14 Substituent Effects – Halogens

X X X

X = F, Cl, Br X = F, Cl, Br

Reactivity (i.e. rate) is a balance between inductive effect (EW) and resonance effect (ED) – larger Cl, Br, I do not push lone pair into pi system as well as F, O, N, which are all first row (2p)

Example:

Cl Cl Cl Cl HNO3, H2SO4 NO2 ++

NO2

NO2 30% 1% 69%

Regioselectivity - second substituent goes o/p – better carbocations

12.15 Multiple Substituent Effects

CH3 O O CH3 O NHCH3 NHCH3

H3C O CH3 Br2, acetic acid Br CH3

AlCl3

CH3 CH3 Cl Cl

99% 87%

CH3 CH3 CH3 CH3

Br2, Fe Br HNO3, H2SO4 NO2

NO2 NO2 C(CH3)3 C(CH3)3

86% 88%

Interplay between power of directing group and size of substituents

9 12.16 Regioselective Synthesis of Disubstituted Derivs.

O O O

CH3 CH3 CH3

Br NO2

CO2H

CH2CH3

Br NO2

Have to be careful about when to introduce each substituent Remember – isomers (e.g. o/p mixtures) may be separated

12.17-12.18 Substitution in Other Aromatic Systems

12.17 Naphthalene

O CH3 O O

CH3CCl CH but not 3 AlCl3

90%

12.18 Heterocycles

SO3H SO3, H2SO4

o N HgSO4, 230 C N

O O

H3C O CH3 CH3 O BF3 O O