22 Reactions of Benzene

7/30/2019 22 Reactions of Benzene

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Chapter 22

Reaction ofBenzene and

its Derivatives


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Reactions of Benzene

Substitution at a ring carbon.

+ +

Chlorobe nzene

Halogenation:

H ClCl2FeCl3 HCl

++

Nitrobenzene

Nitration:

H NO2HNO3H2 SO4

H2 O

Contrast to radical

mechanism for

benzylic hyrdogens


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Reactions of Benzene

+

Benzenesulfonic acid

Sulfonation:

H SO3 HSO3H2 SO4

++

An alkylbenzene

Alkylation:

RRXA lX3

HX

++

Acylation:

An acylbenzene

H RCXA lX3 HX

O

CR

O

H

Friedel Crafts

Friedel Crafts


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Electrophilic Aromatic Substitution

Electrophilic aromatic substitution:

We study several common electrophiles

how each is generated. the mechanism by which each replaces hydrogen.

++

H E

E+

H+


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EAS: General Mechanism

A general mechanism

General question: What are the electrophiles andhow are they generated? Look at particular

reactions.

+ E+

HE

H+slow, rate

determiningStep 1:

Step 2:

E

H+ fast+ H

+E

Electro-phile

Resonance-stabilizedcation intermediate


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Chlorination

Step 1: Generation of the electrophile: a chloronium ion.

Step 2: Attack of the chloroniumion on the ring.

+

+

+

Resonance-stabilized cation intermediate; the positivecharge is delocalized onto three atoms of the ring

+

slow, ratedetermining

Cl

HH

Cl

H

Cl

Cl

Cl Cl ClCl

Cl

Fe

Cl

ClClFeClCl Cl FeCl4

+

A molecular complex

with a positive charge

on chlorine

Ferric chloride

(a Lewis

acid)

Chlorine

(a Lewis

base)

++

An ion pair

containing a

chloronium ion


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Chlorination

Step 3: Proton ejection regenerates the aromatic

character of the ring.

Cl

HCl-FeCl3 Cl HCl FeCl3

Chlorobenzene

fast

Cationintermediate

+++ -

+


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Addition vs Substitution

Energy diagram for the bromination of benzene.


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Nitration (Nitric and Sulfuric Acids)

Generation of the nitronium ion, NO2+

Step 1: Proton transfer to nitric acid.

Step 2: Loss of H2O gives the nitronium ion, a very

strong electrophile. Dehydrated nitric acid.

HSO3 O H H O NO

OHSO4 O N

O

OH

H

Conjugate acidof nitric acid

+ +

Sulfuricacid Nitricacid

The nitroniumion

O N

O

OH

H

OH

H+ O N O


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Nitration,

Step 1: Attack of the nitronium ion) on the aromatic ring.

Step 2: Proton transfer regenerates the aromatic ring.

OH

HO

H

H

HH NO2NO2

OH

HHO

H

HH+ ++ + ++

H NO2 NO2H H NO2

+

+

+

+

Resonance-stabilized cation intermediate

O N O

+

Attack of electrophile as before..


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Synthesis, NitroAmines The nitro group can be reduced to a 1 amino

group.

COOH

NO2

3 H2Ni

COOH

NH2

2H2O

4-Aminoben zoic acid4-Nitroben zoic acid

+

(3 atm)

+

Notice the carboxylic was untouched.


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Sulfonation

Carried out using concentrated sulfuric acid

containing dissolved sulfur trioxide.

Benzenesulfonic acidBenzene

+ SO3 HSO3H2 SO4


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Friedel-Crafts Alkylation

Friedel-Crafts alkylation forms a new C-C bond

between an aromatic ring and an alkyl group.

ClAlCl3

HCl+

Benzene 2-Chloropropane(Isopropyl chlorid e) Cumene(Isopropylbenzene)

+


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Step 1: Formation of an alkyl cation as an ion pair.

Step 2: Attack of the alkyl cation.

Step 3: Proton transfer regenerates the aromatic ring.

+ R+

R

H

R

H

R

H

A resonance-stabilized cation

+

+

+

H

R

Cl AlCl3 R AlCl3 HCl+ ++

R Cl ClAl

Cl

Cl

R Cl

Cl

Cl

Al Cl R+ AlCl4-

An ion pair contain inga carbocation

+-

+

A molecularcomplex


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There are four major limitations on Friedel-Crafts

alkylations:1. Carbocation rearrangements are common

+

Isobutylchloride

tert-ButylbenzeneBenzene

AlCl3+ HClCl

CH3CHCH2 -Cl

CH3

AlCl3 CH3 C-CH2 -Cl-AlCl3

CH3

H

CH3C+

AlCl4-

CH3

CH3Isobutyl chloride

+-

+

a molecular

complexan ion pair


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2. F-C alkylation fails on benzene rings bearing one or

more of these strongly electron-withdrawing groups.

Y

RXAlCl3

SO3 H NO2 NR3+

CF3 CCl3

C N

CHO

CRO

COHO

CORO

CNH2O

+ No reaction

When Y Equals An y of Th ese G roup s, the Benze ne

Ring Doe s N o t Und ergo Fri edel -Crafts Alk ylation


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3. F-C multiple alkylation can occur more rapidly than

monoalkylation. The first alkyl group activates the ringto the second substitution.

4. The steps in the Friedel Crafts Alkylation are reversible

and rearrangments may occur.


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Friedel-Crafts Acylation

Friedel-Crafts acylation forms a new C-C bond

between a benzene ring and an acyl group.

OCl

CH3CCl

O

AlCl3

AlCl3

O

O

HCl

HCl+

Benzene AcetophenoneAcetylchloride

4-Phenylbutanoylchloride

-Tetralone+

+


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The electrophile is an acylium ion.

R-C ClO

Cl

ClAl-Cl

OR-C Cl Al Cl

Cl

Cl

OR-C+ AlCl4

-

Aluminumchloride

An acylchloride

A molecular complexwith a positive charge

charge on chlorine

An ion paircontaining an

acylium ion

+ -

+

(1)

(2)


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An acylium ion is represented as a resonance hybrid

of two major contributing structures.

Friedel-Crafts acylations are free of major

limitation of Friedel-Crafts alkylations; acylium

ions do not rearrange, do not polyacylate (why?),

do not rearrange.

:+ +

complete valenceshells

The more importantcontributing structure

O OR-C R-C::


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Synthesis, Friedel-Crafts Acylation

preparation of unrearranged alkylbenzenes.

+AlCl3

N2H4 , KOH

diethyleneglycol

Isobutylbe nzene2-Methyl-1-phenyl-1-propanone

2-Methylpropanoylchloride

Cl

O

O

What else could be

used here?


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Other Aromatic Alkylations

Carbocations are generated by

treatment of an alkene with a proton acid, mostcommonly H2SO4, H3PO4, or HF/BF3.

treating an alkene with a Lewis acid.

CH3CH=CH2H3PO4

Benzene Propene Cumene

+

+

Benzene Cyclohexene Phenylcyclohexane

AlCl3


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Other Aromatic Alkylations

and by treating an alcohol with H2SO4 or H3PO4.

+

Benzene

H3 PO4+ H2 O

2-Methyl-2-propanol

(tert- Butyl alcohol)

HO

2-Methyl-2-

phe nylpropane

(tert-Butylbenzene)


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Di- and Polysubstitution

Orientation on nitration of monosubstituted

benzenes.

OCH3

Cl

Br

COOHCN

NO2

ortho meta para

ortho +para meta

44 - 55 99 trace

70 - 30 100 trace

37 1 62 99 1

18 80 2 20 8019 80 1 20 80

6.4 93.2 0.3 6.7 93.2

Substituent

CH3 58 4 38 96 4Favor

ortho/para

substitution

Favor

ortho/para

substitution

Favor

ortho/para

substitution

Favor metasubstitution


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Directivity of substituents


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Two ways to characterize the substituent

Orientation:

Some substituents direct preferentially to ortho & para

positions; others to meta positions.

Substituents are classified as eitherortho-para directingor

meta directing toward further substitution.

Rate

Some substituents cause the rate of a second substitution to be

greater than that for benzene itself; others cause the rate to be

lower.

Substituents are classified as activating ordeactivating toward

further substitution.


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-OCH3 is ortho-para directing.

-COOH is meta directing.

OCH3

HNO3 CH3COOH

OCH3NO2

OCH3

NO2

H2 O

p-Nitroanisole(55%)

o-Nitroanisole(44%)

Anisole

+++

COOH

HNO3

H2 SO4NO2

COOH COOH

NO2NO2

COOH

100C

m-Nitro-benzoic

acid(80%)

Benzoicacid

+ ++

o-Nitro-benzoic

acid(18%)

p-Nitro-benzoic

acid(2%)


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Weaklyactivating

Orth

o-paraDirectin

g

Weaklydeactivating

Moderatelyactivating

Strongly

activatingN H2 N HR N R2 OH

N HCR N HCAr

OR

OCArOCR

R

F Cl Br I

: : : : :

::

: : :

:

:

:

:

:

:

:

:

:

:

:

::::

Stronglydeactivating

Moderatelydeactivating

CH

O O

CR COH

SO3 H

CORO

CNH 2

N O2 N H3+

CF3 CCl3MetaDirect

ing

C N

O O O O

OO

Recall the polysubstitution in

FC alkylation.


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Generalizations:

Directivity: Alkyl, phenyl, and all substituents in whichthe atom bonded to the ring has an unshared pair of

electrons are ortho-para directing. All other

substituents are meta directing.

Activation: All ortho-para directing groups except the

halogens are activating toward further substitution.

The halogens are weakly deactivating.


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The order of steps is important.

CH3

K2 Cr2 O7

H2SO4

HNO3

H2 SO4

CH3

NO2

COOH

H2SO4

HNO3

K2 Cr2O7

H2SO4

COOH

NO2

COOH

NO2

m-Nitrobenzoicacid

p-Nitrobenzoic

acid


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Theory of Directing Effects

The rate of EAS is limited by the slowest step in

the reaction. For almost every EAS, the rate-determining step

is attack of E+ on the aromatic ring to give a

resonance-stabilized cation intermediate.

The more stable this cation intermediate, the

faster the rate-determining step and the faster

the overall reaction.


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Theory of Directing Effects

The orientation is controlled by the stability of

the carbocation being formed by attack of the

electrophile.

Products are formed under kinetic control.


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Theory of Directing Effects, ortho-para director.

-OCH3: assume ortho-para attack. Here only para

attack is shown.OCH3

NO2+

fast

+

(d) (e ) (f)

OCH3

H NO2

OCH3

H NO2

OCH3

H NO2

OCH3

H NO2

OCH3

NO2

- H+

+

slow

+

+

+

(g)

::::

: : :

Very stable resonance structure. Why?

o,p director


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Theory of Directing Effects , ortho-para director.

-OCH3; look atmetaattack.

OCH3

NO2+

OCH3

NO2

H

OCH3

NO2

H

OCH3

NO2

H

slow

fast

- H+

+

OCH3

NO2+

++

(a) (b) (c)

No corresponding resonance structure putting

positive charge on oxygen.

o,p director

f i i ff i


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Theory of Directing Effects, meta director.

-CO2H : assume ortho-para attack.

COOH

NO2+

COOH

H NO2

COOH

H NO2

COOH

H NO2

- H+

COOH

NO2

+ slow

fast

(d) (e) (f)

The most disfavoredcontribu ting structure

Meta director

Disfavored because CO2H is

electron withdrawing

Th f Di i Eff di


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Theory of Directing Effects, meta director.

-CO2H; assume metaattack.

COOH

NO2+

COOH

H

NO2

COOH

H

NO2

COOH

H

NO2

-H+

COOH

NO2

+ slow

fast

(a) (b) (c)

Meta director

A ti ti D ti ti R Eff t


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Activating-Deactivating ResonanceEffects

Any resonance effect, such as that of -NH2, -OH,

and -OR, that delocalizes the positive charge onthe cation by has an activating effect toward

further EAS.

Any resonance effect, such as that of -NO2, -CN, -

C=O, and -SO3H, that decreases electron density

on the ring deactivates the ring toward furtherEAS.

A ti ti D ti ti I d ti Eff t


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Activating-Deactivating Inductive Effects

Any inductive effect, such as that of -CH3 or

other alkyl group, that releases electron densitytoward the ring activates the ring toward further

EAS.

Any inductive effect, such as that of halogen,

-NR3+, -CCl3, or -CF3, that decreases electron

density on the ring deactivates the ring towardfurther EAS.

A ti ti D ti ti H l


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Activating-Deactivating: Halogens

For the halogens, the inductive and resonance effects

opposeeach other. Inductive is somewhat stronger. Result: halogens are deactivating but ortho-para

directing.

+++

E

HClCl Cl

H

EE

+:

:

:

: :: ::

N l hili A ti S b tit ti


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Nucleophilic Aromatic Substitution

Aryl halides do not undergo nucleophilic

substitution by either SN1 or SN2 pathways. They do undergo nucleophilic substitutions, but

by two mechanisms.

Benzyne using strong base. Addition/elimination typically with nitro activating

groups.

B I t di t


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Benzyne Intermediates

When heated under pressure with aqueous

NaOH, chlorobenzene is converted to sodiumphenoxide.

Neutralization with HCl gives phenol.

Cl

2NaOHH2O

O-Na

+

NaCl H2O

Sodiumphenoxide

Chloro-benzene

++pressure, 300oC

+

B I t di t ( t b )


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Benzyne Intermediates (strong base)

The same reaction with 2-chlorotoluene gives a

mixture of ortho- and meta-cresol.

The same type of reaction can be brought about using

sodium amide in liquid ammonia.

3-Methylphenol

(m-Cresol)2-Methylphenol

(o-Cresol)

+

CH3Cl OH

CH3 CH3

OH

1. NaOH, heat, pressure

2. HCl, H2O

CH3

Cl

NaNH2NH3 (l)

CH3

NH2

CH3

NH2

NaCl

3-Methylaniline(m-Toluidine)

4-Methylaniline(p-Toluidine)

++(-33

oC)

+

Ben ne Intermediates


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-elimination of HX gives a benzyne intermediate, thatthen adds the nucleophile to give products.

H

CH3

Cl

NaNH2

CH3

A benzyneintermediate

-elimin-ation



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But wait, do we believe this crazy idea? We need some evidence.

A

B



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C

next

The deuterated fluoridebelow exchanges the D with

solvent ammonia although the deuterated bromidedoesnot. This indicates a relatively rapid exchange process for

the fluoro compound.



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explanation

Orientation


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Orientation

The methyl group is essentially just a marker to

allow the observation of the mixture of products.Consider the methoxy group, -OCH3, stabilizing

of positive charge via resonance but also

inductively withdrawing.

The methoxy group is not in resonance with the

negative charge of the anion, Inductive Effect

dominates. Next slide.



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D

Get

same

product Explation

next



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explanation

Addition Elimination (nitro groups)


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Addition-Elimination (nitro groups)

When an aryl halide contains electron-withdrawing

NO2 groups ortho and/or para to X, nucleophilicaromatic substitution takes place readily.

Neutralization with HCl gives the phenol.

ClNO2

NO2

Na2 CO3 , H2 O

O-

Na+

NO2

NO2

100oC

Sodium 2,4-din itro-phenoxide

1-Chloro-2,4-dinitrobenzene

Meisenheimer Complex


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Meisenheimer Complex

Reaction involves formation of reactive intermediate

called a Meisenheimer complex.

N Cl

NO2

O

O

Nu-

Cl

NuN

O

ONO2

N

O

O

NO2

Nu :Cl-fast

slow, ratedetermining

++

+ + +

A Meisenheimer complex

(1)

(2)

Similar to nucleophilic subsititution on carboxylic acid

derivatives.

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22 Reactions of Benzene

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