22-22-11

Reactions of Reactions of Benzene and itsBenzene and itsDerivativesDerivatives

Chapter 22

Chapter 22Chapter 22

22-22-22

Reactions of BenzeneReactions of Benzene

The most characteristic reaction of aromatic compounds is substitution at a ring carbon.

This is Electrophilic Aromatic Substitution (EAS).

+ +

Chlorobenzene

Halogenation:

H ClCl2FeCl3 HCl

++

Nitrobenzene

Nitration:

H NO2HNO3H2 SO4

H2 O

22-22-33

Reactions of BenzeneReactions of Benzene

+

Benzenesulfonic acid

Sulfonation:

H SO3 HSO3

H2 SO4

++

An alkylbenzene

Alkylation:

RRXAlX3 HX

++

Acylation:

An acylbenzene

H RCXAlX3 HX

O

CR

O

H

22-22-44

22.1 22.1 Electrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution

Electrophilic aromatic substitution (EAS):Electrophilic aromatic substitution (EAS): a reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile.

To study• several common types of electrophiles.

• how each is generated.

• the mechanism by which each replaces hydrogen.

++H E

E+

H+

22-22-55

A.A. Chlorination of Benzene Chlorination of Benzene

Step 1: formation of a chloronium ion.

Step 2: attack of the chloronium ion 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

ClFe

Cl

Cl

ClFeClCl 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

22-22-66

ChlorinationChlorination

Step 3: proton transfer regenerates the aromatic character of the ring.

Cl

HCl-FeCl3 Cl HCl FeCl3

Chlorobenzene

fast

Cation intermediate

++

+-

+

22-22-77

EAS: General MechanismEAS: General Mechanism

A general mechanism:

General question: what is the electrophile and how is it generated ?

+ E+HE

H+slow, rate

determiningStep 1:

Step 2:E

H+

fast + H+E

Electro- phile

Resonance-stabilized cation intermediate

22-22-88

Bromination of BenzeneBromination of Benzene

Figure 22.1: Energy diagram for the bromination of benzene.

22-22-99

B.B. Formation of the Nitronium Ion Formation of the Nitronium Ion

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.

HSO3 O H H O NO

OHSO4 O N

O

OH

H

Conjugate acidof nitric acid

+ +

Sulfuricacid

Nitricacid

The nitroniumion

O NO

OH

HO

H

H+ O N O

22-22-1010

Nitration of BenzeneNitration of Benzene

Step 1: attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile).

Step 2: proton transfer regenerates the aromatic ring.

O N O

H NO2 NO2H H NO2

++

+

+

Resonance-stabilized cation intermediate

+

OH

HO

H

H

HH NO2NO2

OH

HHO

H

HH+ ++ + ++

22-22-1111

Reduction of the Nitro GroupReduction of the Nitro Group

A particular value of nitration is that the nitro group can be reduced to a 1° amino group.

Reduction occurs with other reagents such as an active metal (Fe, Sn or Zn) in HCl.

COOH

NO2

3H2Ni

COOH

NH2

2H2O

4-Aminobenzoic acid4-Nitrobenzoic acid

+(3 atm) +

22-22-1212

Sulfonation of Benzene Sulfonation of Benzene

Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide.

Concentrated sulfuric acid containing dissolved sulfur trioxide is fuming sulfuric acid.

The sulfonation reaction is reversible whereas the halogenation and nitration reactions are not.

Benzenesulfonic acidBenzene

+ SO3HSO3H2 SO4

22-22-1313

C.C. Friedel-Crafts Alkylation of Benzene Friedel-Crafts Alkylation of Benzene

Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group.

ClAlCl3

HCl+

Benzene 2-Chloropropane(Isopropyl chloride)

Cumene(Isopropylbenzene)

+

22-22-1414

Friedel-Crafts AlkylationFriedel-Crafts Alkylation

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

Step 2: attack of the alkyl cation on the ring.

Step 3: proton transfer regenerates aromaticity.

+ R+

R

H

R

H

R

H

A resonance-stabilized cation

+

+

+

H

RCl AlCl3 R AlCl3 HCl+ ++

R Cl ClAlCl

Cl

R Cl

Cl

ClAl Cl R+ AlCl4

-

An ion pair containing a carbocation

+-

+

A molecular complex

22-22-1515

Limitations on Friedel-Crafts AlkylationLimitations on Friedel-Crafts Alkylation

There are three major limitations on Friedel-Crafts alkylations.1. carbocation rearrangements are common.

+

Isobutylchloride

tert-ButylbenzeneBenzene

AlCl3 + HClCl

CH3CHCH2-Cl

CH3

AlCl3 CH3C-CH2-Cl-AlCl3

CH3

H

CH3C+ AlCl4

-CH3

CH3Isobutyl chloride

+ -+

a molecularcomplex

an ion pair

22-22-1616

Limitations on Friedel-Crafts AlkylationLimitations on Friedel-Crafts Alkylation

2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron-withdrawing groups.

Y

RXAlCl3

SO3H NO2 NR3+

CF3 CCl3

C N

CHO

CRO

COHO

CORO

CNH2

O

+ No reaction

When Y Equals Any of These Groups, the BenzeneRing Does Not Undergo Friedel-Crafts Alkylation

22-22-1717

Limitations on Friedel-Crafts Alkylation Limitations on Friedel-Crafts Alkylation

3. Polyalkylation: An alkyl group added to the ring activates the ring and further alkylation occurs.

Limitations 1 & 3 do not apply to Friedel-Crafts Acylation reactions.

ClAlCl3 HCl+

Benzene

+CH3

CH3

CH3

CH3

x

22-22-1818

Friedel-Crafts Acylation of BenzeneFriedel-Crafts Acylation of Benzene

Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group.

OCl

CH3CClO

AlCl3

AlCl3

O

O

HCl

HCl+

Benzene AcetophenoneAcetylchloride

4-Phenylbutanoylchloride

-Tetralone

+

+

22-22-1919

Friedel-Crafts AcylationFriedel-Crafts Acylation

The electrophile is an acylium ion.

R-C Cl

O

Cl

Cl

Al-Cl

O

R-C Cl Al Cl

Cl

Cl

O

R-C+ AlCl4-

Aluminumchloride

An acyl chloride

A molecular complexwith a positive charge

charge on chlorine

An ion pair containing an

acylium ion

+ -

••

••••

+(1)

(2)

••

••

22-22-2020

Friedel-Crafts AcylationFriedel-Crafts Acylation

• an acylium ion is a resonance hybrid of two major contributing structures.

F-C acylations are free of two major limitation of F-C alkylations; acylium ions do not rearrange nor do they polyacylate.

:+ +

complete valence shells

The more importantcontributing structure

O OR-C R-C::

22-22-2121

Friedel-Crafts AcylationFriedel-Crafts Acylation

A special value of F-C acylations is preparation of unrearranged alkylbenzenes.

+AlCl3

N2H4, KOHdiethylene glycol Isobutylbenzene2-Methyl-1-

phenyl-1-propanone

2-Methylpropanoyl chloride

Cl

O

O

Wolff-Kishner reduction, pg 623

22-22-2222

D.D. Other Aromatic Alkylations Other Aromatic Alkylations

Carbocations are also generated from alkenes and alcohols:• by treatment of an alkene with a protic acid, most

commonly H2SO4, H3PO4, or HF/BF3,

CH3CH=CH2H3PO4

Benzene Propene Cumene

+

22-22-2323

Other Aromatic AlkylationsOther Aromatic Alkylations

• by treating an alkene with a Lewis acid,

• and by treating an alcohol with H2SO4 or H3PO4.

+

Benzene

H3PO4 + H2O

2-Methyl-2-propanol(tert-Butyl alcohol)

HO

2-Methyl-2-phenylpropane(tert-Butylbenzene

+

BenzeneCyclohexenePhenylcyclohexane

AlCl3

22-22-2424

Di- and Polysubstitution of BenzeneDi- and Polysubstitution of Benzene

Orientation:• certain substituents direct preferentially to ortho &

para positions; others to meta positions.

• substituents are classified as either ortho-paraortho-para directingdirecting or meta directingmeta directing toward further substitution.

Rate:• certain 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 activatingactivating or deactivatingdeactivating toward further substitution.

22-22-2525

Di- and PolysubstitutionDi- and Polysubstitution

• -OCH3 is ortho-para directing.

• -CO2H is meta directing.

OCH3

HNO3 CH3COOH

OCH3NO2

OCH3

NO2

H2O

p-Nitroanisole (55%)

o-Nitroanisole (44%)

Anisole

+++

COOH

HNO3H2SO4

NO2

COOH COOH

NO2NO2

COOH

100°C

m-Nitro-benzoic

acid(80%)

Benzoicacid

+ ++

o-Nitro-benzoic

acid(18%)

p-Nitro-benzoic

acid(2%)

22-22-2626

Di- and Polysubstitution, Table 22.2Di- and Polysubstitution, Table 22.2

Weakly activating

Ort

ho-p

ara

Dir

ect

ing

Weakly deactivating

Moderately activating

Strongly activating NH2 NHR NR2 OH

NHCR NHCAr

OR

OCArOCR

R

F Cl Br I

: : : : :::

: : ::

::

::

::

::

:: ::::

Strongly deactivating

Moderately deactivating

CH

O O

CR COH

SO3H

CORO

CNH2

NO2 NH3+ CF3 CCl3M

eta

Dir

ect

ing

C N

O O O O

OO

22-22-2727

Di- and PolysubstitutionDi- and Polysubstitution

From the information in Table 21.1, we can make these generalizations:• alkyl, phenyl, and all other substituents in which

the atom bonded to the ring has an unshared pair of electrons are ortho-para directing; all other substituents are meta directing.

• all ortho-para directing groups except the halogens are activating toward further substitution; the halogens are weakly deactivating.

22-22-2828

22.2 22.2 A.A. Di- and Polysubstitution, Table 22.1Di- and Polysubstitution, Table 22.1

Orientation on nitration of monosubstituted benzenes.

OCH3

Cl

Br

COOH

CN

NO2

ortho meta paraortho +para meta

44 - 55 99 trace

70 - 30 100 trace

37 1 62 99 1

18 80 2 20 80

19 80 1 20 80

6.4 93.2 0.3 6.7 93.2

Substituent

CH3 58 4 38 96 4

22-22-2929

Di- and PolysubstitutionDi- and Polysubstitution

• the sequence of reactions is important.

CH3

K2Cr2O7

H2SO4

HNO3

H2SO4

CH3

NO2

COOH

H2SO4

HNO3

K2Cr2O7

H2SO4

COOH

NO2

COOH

NO2

m-Nitrobenzoicacid

p-Nitrobenzoic acid

22-22-3030

B.B. Theory of Directing Effects 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.

22-22-3131

Theory of Directing EffectsTheory of Directing Effects

For ortho-para directors, ortho-para attack forms a more stable cation than meta attack.• ortho-para products are formed faster than meta

products. For meta directors, meta attack forms a more

stable cation than ortho-para attack• meta products are formed faster than ortho-para

products.

22-22-3232

Theory of Directing EffectsTheory of Directing Effects

• -OCH3 : events during an unfavored meta attack.

OCH3

NO2+

OCH3

NO2

H

OCH3

NO2

H

OCH3

NO2

H

slow

fast-H+

+

OCH3

NO2+

++

(a) (b) (c)

Only three resonance structures and the cation never appears on oxygen.

22-22-3333

Theory of Directing EffectsTheory of Directing Effects

• -OCH3 : events during a favored ortho-para attack.

OCH3

NO2+

fast

+

(d) (e) (f)

OCH3

H NO2

OCH3

H NO2

OCH3

H NO2

OCH3

H NO2

OCH3

NO2

-H+

+

slow

+

+

+

(g)

::::

: : :

Four resonance structures here and the cation does appear on oxygen.

22-22-3434

Theory of Directing EffectsTheory of Directing Effects

• -CO2H : events during a favored meta attack.

COOH

NO2+

COOH

H

NO2

COOH

H

NO2

COOH

H

NO2

-H+

COOH

NO2

+ slow

fast

(a) (b) (c)

The cation never appears adjacent to the (+) carbon of C=O.

22-22-3535

Theory of Directing EffectsTheory of Directing Effects

• -CO2H : events during an unfavored ortho-para attack.COOH

NO2+

COOH

H NO2

COOH

H NO2

COOH

H NO2

-H+

COOH

NO2

+ slow

fast

(d) (e) (f)The most disfavoredcontributing structure

The cation appears adjacent to a (+) carbon of C=O.

22-22-3636

C.C. Activating-Deactivating Effects Activating-Deactivating Effects

Any resonance effectAny resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation intermediate lowers the activation energy for its formation, and has an activating effect toward further EAS.

Any resonance or inductive effectAny resonance or inductive effect, such as that of -NO2, -CN, -CO, and -SO3H, that decreases electron density on the ring deactivates the ring toward further EAS.

22-22-3737

Activating-DeactivatingActivating-Deactivating

Any inductive effectAny inductive effect, such as that of -CH3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS.

Any inductive effectAny inductive effect, such as that of halogen, -NR3

+, -CCl3, or -CF3, that decreases electron density on the ring deactivates the ring toward further EAS.

22-22-3838

Activating-DeactivatingActivating-Deactivating

• for the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger with respect to deactivation.

• the net effect is that halogens are deactivating but ortho-para directing.

++

+E

HClCl Cl

H

EE

+

::

:: :: ::

22-22-3939

Relative rates of EASRelative rates of EAS

Relative rates of reaction for substituted benzenes compared to unsubstituted benzene.

rel. rate

Aniline 106 strongly activating NH2

Toluene 25 weakly activating CH3

Benzene 1 neutral

Chlorobenzene 0.03 weakly deactivating Cl

Nitrobenzene 10-6 strongly deactivating NO2

22-22-4040

22.3 22.3 Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution

Aryl halides do not undergo nucleophilic aromatic substitution (NAS) by either SN1 or SN2.

They do undergo nucleophilic substitutions, but by mechanisms quite different from those of nucleophilic aliphatic substitution.

There are two common mechanisms:• The benzyne mechanism.

• The addition-elimination mechanism. Nucleophilic aromatic substitutions are far

less common than electrophilic aromatic substitutions.

22-22-4141

A.A. Benzyne Intermediates Benzyne Intermediates

When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide.• neutralization with HCl gives phenol.

Cl

2NaOHH2O

O-Na

+

NaCl H2O

Sodium phenoxide

Chloro-benzene

++pressure, 300oC

+

22-22-4242

Benzyne IntermediatesBenzyne Intermediates

• the same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol.

• the same type of reaction can be brought about using of 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)

++(-33oC)

+

22-22-4343

Benzyne IntermediatesBenzyne Intermediates

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

H

CH3

Cl

NaNH2

CH3

A benzyneintermediate

-elimin-ation

Benzyne is unstable due to poor orbital overlap,brackets mean that this is a transient intermediate.

22-22-4444

B.B. Addition-Elimination Addition-Elimination

• when an aryl halide contains electron-withdrawing NO2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place more readily.

• neutralization with HCl gives the phenol.

ClNO2

NO2

Na2CO3, H2O

O- Na

+

NO2

NO2

100oC

Sodium 2,4-dinitro- phenoxide

1-Chloro-2,4-dinitrobenzene

22-22-4545

Meisenheimer ComplexMeisenheimer Complex

• reaction involves a Meisenheimer complex intermediate.

N Cl

NO2

O

O

Nu-

Cl

NuN

O

ONO2

N

O

O

NO2

Nu :Cl -fast

slow, ratedetermining

++

+ + +

A Meisenheimer complex

(1)

(2)

22-22-4646

End Chapter 22End Chapter 22

Reaction ofReaction ofBenzene and Benzene and its Derivativesits Derivatives