22-22-11

Chapter 22Chapter 22

Reaction ofReaction ofBenzene and Benzene and its Derivativesits Derivatives

22-22-22

Reactions of BenzeneReactions of Benzene

Substitution at a ring carbon.

+ +

Chlorobenzene

Halogenation:

H ClCl2FeCl3 HCl

++

Nitrobenzene

Nitration:

H NO2HNO3H2 SO4

H2 O

Contrast to radical mechanism for benzylic hyrdogens

22-22-33

Reactions of BenzeneReactions of Benzene

+

Benzenesulfonic acid

Sulfonation:

H SO3HSO3H2 SO4

++

An alkylbenzene

Alkylation:

RRXAlX3 HX

++

Acylation:

An acylbenzene

H RCX AlX3 HXO

CRO

H

Friedel Crafts

Friedel Crafts

22-22-44

Electrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution

ElectrophilicElectrophilic aromatic substitution: aromatic substitution:

We study several common electrophiles• how each is generated.• the mechanism by which each replaces hydrogen.

++H E

E+

H+

22-22-55

EAS: General MechanismEAS: General Mechanism

A general mechanism

General question: What are the electrophiles and how are they generated? Look at particular reactions.

+ E+HE

H+slow, rate

determiningStep 1:

Step 2:E

H+

fast + H+E

Electro- phile

Resonance-stabilized cation intermediate

22-22-66

ChlorinationChlorination

Step 1: Generation of the electrophile: 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

22-22-77

ChlorinationChlorination

Step 3: Proton ejection regenerates the aromatic character of the ring.

Cl

HCl-FeCl3 Cl HCl FeCl3

Chlorobenzene

fast

Cation intermediate

++

+-

+

22-22-88

Addition vs SubstitutionAddition vs Substitution

Energy diagram for the bromination of benzene.

22-22-99

Nitration (Nitric and Sulfuric Acids)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 NO

OH

HO

H

H+ O N O

22-22-1010

Nitration, 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…..

22-22-1111

Synthesis, Nitro Synthesis, Nitro AminesAmines

The nitro group can be reduced to a 1° amino group.

COOH

NO2

3H2Ni

COOH

NH2

2H2O

4-Aminobenzoic acid4-Nitrobenzoic acid

+(3 atm) +

Notice the carboxylic was untouched.

22-22-1212

SulfonationSulfonation

Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide.

Benzenesulfonic acidBenzene

+ SO3HSO3H2 SO4

22-22-1313

Friedel-Crafts AlkylationFriedel-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 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.

Step 3: Proton transfer regenerates the aromatic ring.

+ 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

Friedel-Crafts AlkylationFriedel-Crafts Alkylation

There are four 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

CH3

Isobutyl chloride

+-

+

a molecularcomplex

an ion pair

22-22-1616

Friedel-Crafts AlkylationFriedel-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

Friedel-Crafts AlkylationFriedel-Crafts Alkylation

3. F-C multiple alkylation can occur more rapidly than monoalkylation. The first alkyl group activates the ring to the second substitution.

CH3Cl

AlCl3

4. The steps in the Friedel Crafts Alkylation are reversible and rearrangments may occur.

CH3Cl

AlCl3

AlCl3

22-22-1818

Friedel-Crafts Friedel-Crafts AcylationAcylation

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 ClO

Cl

ClAl-Cl

OR-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 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 valence shells

The more importantcontributing structure

O OR-C R-C::

22-22-2121

Synthesis, Synthesis, Friedel-Crafts AcylationFriedel-Crafts Acylation

preparation of unrearranged alkylbenzenes.

+AlCl3

N2H4, KOHdiethylene glycol Isobutylbenzene2-Methyl-1-

phenyl-1-propanone

2-Methylpropanoyl chloride

Cl

O

O

What else could be used here?

22-22-2222

Other Aromatic AlkylationsOther Aromatic Alkylations

Carbocations are generated by • treatment of an alkene with a proton acid, most

commonly H2SO4, H3PO4, or HF/BF3.

• treating an alkene with a Lewis acid.

CH3CH=CH2H3PO4

Benzene Propene Cumene

+

+

Benzene Cyclohexene Phenylcyclohexane

AlCl3

22-22-2323

Other Aromatic AlkylationsOther Aromatic Alkylations

• 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)

22-22-2424

Di- and PolysubstitutionDi- and Polysubstitution

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 4Favor ortho/para substitution

Favor ortho/para substitution

Favor ortho/para substitution

Favor meta substitution

22-22-2525

Directivity of substituentsDirectivity of substituents

XXX X

E

E

E

E

+ +

ortho and para, appear together X is o,p director

metaX is m director

22-22-2626

Di- and PolysubstitutionDi- and Polysubstitution

Two ways to characterize the substituent • Orientation:

• Some substituents direct preferentially to ortho & para positions; others to meta positions.

• Substituents are classified as either ortho-para directingortho-para directing or meta directing 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 activatingactivating or deactivatingdeactivating toward further substitution.

22-22-2727

Di- and PolysubstitutionDi- and Polysubstitution

• -OCH3 is ortho-para directing.

• -COOH 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%)

22-22-2828

Di- and PolysubstitutionDi- and Polysubstitution

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

Recall the polysubstitution in FC alkylation.

22-22-2929

Di- and PolysubstitutionDi- and Polysubstitution

Generalizations:• Directivity: Alkyl, phenyl, and all 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.

• Activation: All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating.

22-22-3030

Di- and PolysubstitutionDi- and Polysubstitution

• The order of steps is important.

CH3

K2Cr2O7

H2SO4

HNO3

H2SO4

CH3

NO2

COOH

H2SO4

HNO3

K2Cr2O7

H2SO4

COOH

NO2

COOH

NO2

m-Nitrobenzoicacid

p-Nitrobenzoic acid

22-22-3131

Theory of Directing EffectsTheory 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.

22-22-3232

Theory of Directing EffectsTheory 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.

22-22-3333

Theory of Directing Effects, ortho-para director.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

22-22-3434

Theory of Directing Effects , ortho-para director.Theory of Directing Effects , ortho-para director.

• -OCH3; look at meta attack.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

22-22-3535

Theory of Directing Effects, meta director.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 disfavoredcontributing structure

Meta director

Disfavored because CO2H is electron withdrawing

22-22-3636

Theory of Directing Effects, meta director.Theory of Directing Effects, meta director.

• -CO2H; assume meta attack.

COOH

NO2+

COOH

H

NO2

COOH

H

NO2

COOH

H

NO2

-H+

COOH

NO2

+ slow

fast

(a) (b) (c)

Meta director

22-22-3737

Activating-DeactivatingActivating-Deactivating ResonanceResonance Effects Effects

Any resonance effectAny resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation by has an activating effect toward further EAS.

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

22-22-3838

Activating-DeactivatingActivating-Deactivating InductiveInductive Effects Effects

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.

22-22-3939

Activating-Deactivating: Activating-Deactivating: HalogensHalogens

• For the halogens, the inductive and resonance effects oppose each other. Inductive is somewhat stronger.

• Result: halogens are deactivating but ortho-para directing.

++

+E

HClCl Cl

H

EE

+

::

:: :: ::

22-22-4040

Nucleophilic Aromatic SubstitutionNucleophilic 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.

22-22-4141

BenzyneBenzyne Intermediates 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 Intermediates (strong base) 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)

++(-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

CH3

+

CH3

NH2

NH2

NH2-

CH3

+

CH3

NH2

NH2

NH2-

22-22-4444

Benzyne IntermediatesBenzyne Intermediates

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

Cl

* NaNH2

NH2

*

NH2

*+

47% 53%

Cl

CH3H3CO

NaNH2NR

A

B

22-22-4545

Benzyne IntermediatesBenzyne Intermediates

D

F

H

F

NaNH2

NH3

but

D

Br

D

NH2

NaNH2

NH3

NH2rapid

slow

+

H

NH2NH2

D

+

C

next

The deuterated fluoride below exchanges the D with solvent ammonia although the deuterated bromide does not. This indicates a relatively rapid exchange process for the fluoro compound.

22-22-4646

Benzyne IntermediatesBenzyne Intermediates

X

+ NH2-

H

X

k1

k-1

X

k2

+ NH3

X = F k-1 >> k2

X = Br k-1 << k2

explanation

22-22-4747

OrientationOrientation

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.

22-22-4848

Benzyne IntermediatesBenzyne Intermediates

D

OCH3

Br

OCH3

NH2

and

OCH3OCH3

NH2

Br

NaNH2

NaNH2

Get same product Explation

next

22-22-4949

Benzyne IntermediatesBenzyne Intermediates

OCH3

Br

OCH3

Br

NaNH2

NaNH2

H

OCH3

Br

only H to remove

preferred due to inductive effect

OCH3

Br

H

OCH3

NH2-

OCH3

NH2-

OCH3

NH2

preferred due to inductive effect

explanation

22-22-5050

Addition-Elimination (nitro groups)Addition-Elimination (nitro groups)

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

22-22-5151

Meisenheimer ComplexMeisenheimer 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.