BenZene Ractions

Dr Md Ashraful Alam

Assistant Professor

Department of Pharmaceutical Sciences

• Benzene does not undergo electrophilic addition

• It undergoes electrophilic aromatic substitution maintaining the aromatic core

• Electrophilic aromatic substitution replaces a proton on benzene with a.nother electrophile

2

3

electrophilic aromatic substitution

Electrophilic Aromatic Substitution

HE

E

HE

+ H-base:base

Ortho-Para and Meta Directing Substituents

• When substituted benzenes undergo further substituents, the substituent group present in the benzene derivative will influence electrophilic substitution in 2 ways which are:

i) Reactivity

ii)Orientation

EFFECTS OF SUBSTITUENTS ON THE REACTIVITY OF ELECTROPHILIC

AROMATIC SUBSTITUTION• Substituent group present in the benzene ring can

influence the rate of reaction of further substitutions.

• Electron-donating groups make the ring more reactive (called activating groups) thus influence the reaction become faster.

• Electron-withdrawing groups make the ring less reactive (called deactivating groups) thus influence the reaction become slower.

• A substituents group already in the ring influences the position of further electrophilic substitution whether at ortho, meta or para position.

• Ortho-para directors: the groups that tend to direct electrophilic substitution to the C2 and C4 positions.

• Meta directors: the groups that tend to direct electrophilic substitution to the C3 position.

EFFECTS OF SUBSTITUENTS ON THE ORIENTATION OF ELECTROPHILIC

AROMATIC SUBSTITUTION

Effetcs of substituent groups on the benzene ring

Activating groups (electron donating)

Deactivating groups

(electron-withdrawing)

-NH2 -R

-OH

-OR

-NHCOCH3

-F

-Cl

-Br

-I

ortho-para directors ortho-para directors

meta directors

C

O

R

C

O

OH

C

O

OR

SO3H

C N

NO2

NR3

Disubstituted Benzenes : Orientation

Orientation Effects of Substituents in Electrophilic Aromatic Substitution :

Ortho , para directors Meta directors

-OH, -OR-NH2, -NHR, -NR2-C6H5-CH3, -R (alkyl)-F, -Cl, -Br, -I

-NO2-SO3H-COOH, -COOR-CHO, -COR-CN

OH OH

NO2

NO2

nitration

NO2

NO2

nitration+

OH

NO2o-Nitrophenol p-Nitrophenol

53 47

10

Substituent Effects in Aromatic Rings • Substituents can cause a compound to be (much)

more or (much) less reactive than benzene• Substituents affect the orientation of the reaction

– the positional relationship is controlled– ortho- and para-directing activators, ortho- and para-

directing deactivators, and meta-directing deactivators

11

Activators/Deactivators

Specific Electrophilic Aromatic : Substitution Reactions

X2 , FeX3

Halogenation

X

+ HX (X=Cl, Br)

RCl, AlCl 3

Alkylation

R

+ ClH

HONO2 , H2SO4

Nitration

NO2

+ OH2

SO3 , H2SO4

Sulfonation

SO3H

EAS Reactions of Benzene

Br

NO2

SO3H

CR

O

Cl

IR

CHO

• Benzene’s electrons participate as a Lewis base in reactions with Lewis acids

– Lewis acid: electron pair acceptor

– Lewis base: electron pair donor

• The product is formed by loss of a proton, which is replaced by a halogen

14

Bromination / Chlorination

H BrBr2, FeBr3

+ HBr

H ClCl2, FeCl3

+ HCl

Bromination Mechanism

Nitration

HNO3, H2SO4NO2

+ H2O

HNO3 + H2SO4 NO2+ + H2O + HSO4

-

Formation of electrophile

Nitration Mechanism

Nitration of Toluene

Sulfonation is Reversible

HSO3, H2SO4

SO3Hfuming sulfuric acid

S

O

OO H OSO3H

SO3H

HOSO3H

Desulfonation

Friedel-Crafts Acylation

RCCl, AlCl3

O C

O

R+ HCl

1st, Formaton of Electrophile

C

O

R Cl AlCl3

+ -

RC

O

R C O AlCl4

acylium ion

Acylation Mechanism

C

O

R

C

O

RH Cl AlCl3

CR

O

+ HCl

Intermediate is Resonance-Stabilized

C

O

RH

C

O

RH

C

O

RH

An Acylation

CH3

CH3

CH3CH2CH2CH2CCl

O

TiCl4 in CH2Cl2

CCH2CH2CH2CH3

OCH3

CH3

+ HCl

Friedel-Crafts Alkylationmany more limitations

RX, AlCl3R

+ HCl

Mechanism

CH3 C

CH3

CH3

Cl AlCl3 C

CH3

CH3

CH3

t-butyl carbocation

AlCl4

CH3 C

CH3

CH3

(CH3)3C

H

(CH3)3C (CH3)3C

resonance stabilized intermediate

Cl AlCl3 (CH3)3C

+ HCl(+ AlCl3)

Carbocation Generated From Alkene

Unexpected Product?

CH3CH2CH2CH2Cl, AlCl 3

CH2CH2CH2CH3

CHCH2CH3

CH3

minor product

major product

Carbocations Rearrange…

CH3CH2CH2CH2 Cl AlCl3 CH3CH2CHCH2

H

CH3CH2CHCH3

hydride shift

2o

1o

1o RX Typically Undergoes Shift

Side Chain Reactions

O

H2, Pd/C

in ethanol

1) Reduction of Aromatic Ketones

Straight-chain Alkylation can be Accomplished in 2 steps:

Acylation, then Reduction

CH2CH2CH3

CCH2CH3

O

CH3CH2CH2Cl

AlCl3 minor

CH(CH3)2

+

CH3CH2CCl

AlCl3

O

major

H2, Pd/C

2) Oxidation of Alkyl SubstituentsCH3

KMnO4, H2O

COH

O

KMnO4

H2O

CO2H

CH3

CH(CH3)2

KMnO4, H2OCO2H

CO2H

3) Benzylic Bromination with NBS

H

NBS, CCl4, h

Br

NBr

O

O

NBS

benzylic hydrogen

N-Bromosuccinimide

4) Alkali Fusion of Sulfonic Acids

phenol

SO3H1) NaOH, 300 C

2) H3O+

OHo

5) Reduction of Nitro Groups

NO21) SnCl2, HCl2) NaOH

or H2 on Pt

NH2

Directing Effects

EDG EWG

electron donating groups electron withdrawing groups activate ring deactivate ring

atom attached isusually sp3

atom attached isusually sp or sp2

ortho/para-Directing Activating Groups

OCH3 OCH3 OCH3 OCH3

OCH3

+

- -

-

Nitration of Anisole

Nitration Affords ortho and para Products

OCH3

HNO3, H2SO4

OCH3

NO2

OCH3

NO2

+

ortho para

Activating ortho/para directors

meta-Directing Deactivating Groups

CH

O

CH

O

CH

O

CH

O

CH

O

+

+ +

-

ortho and para positions

are deactivated toward

EAS

Electron-Withdrawing Nitro Group Directs meta

meta Directors

Comparison

CH3

CF3

Br2, FeBr3

ortho meta para

Brominated product

63 3 34

6 91 3

ortho meta para

rel. rate

25

0.000025

rate rel. to benzene

More Limitations with Friedel Crafts Reactions

Cl

Ring must be at least as activated (reactive) as

NO2 ClCCH3, AlCl3

O

No Reaction

Cl

CH2CH3

+ orthoCH3CH2Cl, TiCl4

Substituent Summary

Halogens are the AnomolyDeactivators and o,p-Directors

Br

CH3CH2Cl

AlCl3

Br

CH2CH3

CH2CH3

Br

+

rel. rate = 0.5

Inductively withdrawing, hence deactivatingResonance donation causes o,p directing

Reactions of Rings With Two or More Substituents

NO2

OCH3 OCH3

NO2

ClCl2, FeCl3

Activating Group Controls Reaction

The (More) Activated Ring Reacts

CO

OH2SO4

SO3

CO

O

SO3H

deactivated activated(+ some ortho)

*

Mixtures with Conflicting Directing Effects

Provide the Reagents

NH2

C(CH3)3

Br

Must Acylate FirstNH2

ClCCH2CH2CH2CH3

O

AlCl3

O meta director

HNO3

H2SO4

O

NO2

H2, Pt/C

Sulfonic Acid Blocks para Position C(CH3)3

Br

H(CH3)3CBr

AlCl3

C(CH3)3

SO3, H2SO4

SO3H

C(CH3)3

Br2, FeBr3

C(CH3)3

SO3H

Br

H3O+

blocks para

Give the Reagents

CO2H

O

CH3Cl

Provide the Reagents

CH2CH3

OHBr

CH2CH3

OHBr

1) ClCCH3, AlCl3

O

2) SO3, H2SO4

3) Br2, FeBr3

4) H2 Pd/C5) NaOH, 300 C

o

6) H3O+

O O

SO3H

O

SO3HBr SO3HBr

1)

2) 3) 4)

5,6)

Provide the Reagents

HO2C

HO2C1)

Cl

AlCl3

2) Cl

O AlCl33) KMnO4, H2O

4) H2, Pd/C

5) NBS, h6) NaOCH3 in CH3OH, heat

(E2 elim of HBr)

1)

O

2)

O

HO2C3)

HO2C

HO2C

Br

4)

5)

6) workup w/ H3O+

65

Reactions of Benzene