Lecture Notes

Paper – II

Group-B (Organic Chemistry)

Unit – 5 (Aromatic compound)

Part-4

For

B.Sc. (Part-4)

Honours & Subsidiary

Jai Prakash University, Chapra

By

Dr. Tanu Gupta

Assistant Professor

DEPARTMENT OF CHEMISTRY

RAJENDRA COLLEGE, CHAPRA

(+) (+) H

(+) (+)

Electrophilic Substitution Reactions of

Substituted Benzenes Halogens are deactivating groups, yet they are ortho, para-directors because the halogens

are strongly electronegative, withdrawing electron density from a carbon atom through

the σ-bond, and the halogens have nonbonding electrons that can donate electron density

through π-bonding. If an electrophile reacts at the ortho or para position, the positive

charge of the sigma complex is shared by the carbon atom bearing the halogen. The

nonbonding electrons of the halogen can further delocalize the charge onto the halogen,

giving a halonium ion structure. This resonance stabilization allows a halogen to be pi-

donating, even though it is sigma-withdrawing.

ortho attack

Br

para attack

Br

meta attack

Br

E

(+)

E

(+)

H

(+)

(+)

(+)

H

E

bromonium ion

Reaction at the meta position gives a sigma complex whose positive charge is not

delocalized onto the halogen-bearing carbon atom. Therefore, the meta

intermediate is not stabilized by the halonium ion structure. Scheme 1 illustrates

the preference for ortho and para substitution in the nitration of chlorobenzene.

Cl Cl Cl Cl

chlorobenzene

HNO3

H2SO4

NO2

NO2

NO2

ortho-isomer meta-isomer para-isomer

(35% yield) (1% yield) (64% yield)

Scheme 1

Ortho-para ratio differs with the size of the substituents. Nitration of toluene

preferably gives ortho as the major product where the activating substituent is

methyl group. Electrophilic substitution reaction of ethyl substituted benzene,

however, gives ortho and para isomers equally. Bulky substituent such as tert-

butyl benzene preferably gives para-isomer as the major product (Scheme 2).

CH3 CH3 CH3

HNO3

H2SO4

NO2

NO2

toluene ortho-isomer para-isomer

major minor

CH2CH3 CH2CH3 CH2CH3

HNO3

H2SO4

NO2

NO2

ethylbenzene ortho-isomer para-isomer

50% 50%

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

HNO3

H2SO4

NO2

NO2

tert-butylbenzene ortho-isomer para-isomer minor

Scheme 2

major

3

3

2

Benzenes which are having a meta director (a deactivating group) on the ring, will

be too unreactive to undergo either Friedel-Crafts alkylation or Friedel-Crafts

Acylation (Scheme 3).

SO3H

H C Cl AlCl3

No reaction

benzenesulfonic acid

NO2

nitrobenzene

O

H C Cl AlCl3

No reaction

Scheme 3

Aniline and N-substituted anilines also do not undergo Friedel-Crafts reactions

because the lone pair on the amino group will form complex with the Lewis acid

and converting the substituent into a deactivating meta director. Tertiary aromatic

amines, however, can undergo electrophilic substitution because the tertiary

amino group is a strong activator (Scheme 4).

NH2

AlCl3

H N AlCl3

aniline

N(CH3)3 N(CH3)3 N(CH3)3

1) HNO3

CH3COOH

2) OH- N,N-dimethylaniline

NO2

NO2

ortho-isomer para-isomer

Scheme 4

Phenols are highly reactive substrates for electrophilic aromatic substitution

because of the presence of a strong activating group. So phenols can be alkylated

or acylated using relatively weak Friedel-Crafts catalysts such as HF (Scheme 5).

OH OH OH OH

HF H H

CH3

CH3

3C C 3

phenol 2-propanol H3C

CH3

4-isopropylphenol 2-isopropylphenol

Scheme 5

Phenoxide ions, generated by treating a phenol with sodium hydroxide, are even

more reactive than phenols toward electrophilic aromatic substitution. It gives

tribromosubstituted phenol when reacts with excess bromine and salicylic acid

when reacts with carbon dioxide (Scheme 6).

Br2

x

OH Br Br

(e cess)

OH O

NaOH

H2O

phenol phenoxide

ion

1. CO2

2. H+

Br

2,4,6-tribromophenol

OH

COOH

salicylic acid

Scheme 6

Nucleophilic Substitution Aryl halides do not react with nucleophiles under the standard reaction conditions

because the electron clouds of aryl ring repel the approach of a nucleophile. Nucleophiles

can displace halide ions from aryl halides, if there are strong electron-withdrawing

groups ortho or para to the halide. This class of reactions is called nucleophilic aromatic

substitution reaction (Scheme 7).

Cl

NO2

NO2

2 NH3

heat

pressure

NH2

NO2

NO2

1- chloro-2,4-dinitrobenzene 2,4-dinitroaniline

O2N

Cl

NO2

H2O, 40C

O2N

OH

NO2

NO2 NO2

2- chloro-1,3,5-trinitrobenzene picric acid

Scheme 7

Electron-withdrawing substituents such as nitro group make the ring reactive

towards nucleophilic aromatic substitution but without at least one powerful

electron-withdrawing group, the nucleophilic aromatic substitutions would be

difficult. The mechanism of nucleophilic aromatic substitution cannot be the SN2

mechanism because aryl halides cannot achieve the correct geometry for back-

side approach of a nucleophile. The SN1 mechanism also cannot be involved.

Consider the reaction of 2,4-dinitrochlorobenzene with a nucleophile (Scheme 8).

When a nucleophile attacks the carbon bearing the chlorine, a negatively charged

sigma complex results. The negative charge is delocalized over the ortho and

para carbons of the ring and further delocalized into the electron-withdrawing

nitro groups. Loss of chloride from the sigma complex gives the nucleophilic

substituted product.

Step 1: Attack by the nucleophile gives a sigma complex

Cl

NO2

NO2

Nu-

slow

Cl Nu

NO2

NO2

Cl Nu O N

O

Cl Nu O N

O

Cl Nu O N

O

Cl Nu O N

O

N N

O O O O N N

O O O O sigma complex

Step 2: Loss of leaving group gives the product

Cl Nu

NO2

NO2

fast

-Cl-

Scheme 8

Nu

NO2

NO2

The leaving group ability of halogen in nucleophilic aromatic substitution reaction

is following the order: F > Cl > Br > I. The incoming group should be a stronger

base than the group that is being replaced (Scheme 9).

F

MeO-

OMe

F-

NO2 NO2

1-fluoro-4-nitrobenzene 1-methoxy-4-nitrobenzene

Br

CH3

HN

NO2

NO2 H3C NH2

OH-

NO2

NO2 H2O

1-bromo-2,4-dinitrobenzene N-ethyl-2,4-dinitroaniline

Scheme 9

Benzyne Mechanism

Although chlorobenzene does not contain an electron-withdrawing group, it can undergo

a nucleophilic substitution reaction in the presence of a very strong base but the incoming

substituent does not always end up on the carbon vacated by the leaving group. For

example, when chlorobenzene is treated with amide ion in liquid ammonia, aniline is

obtained as the product. Half of the product has the amino group attached to the carbon

vacated by the leaving group, but the other half has the amino group attached to the

carbon adjacent to the carbon vacated by the leaving group. This is confirmed by isotopic

labeling method (Scheme 11).

Cl NH2

* NaNH2 *

liq. NH3

NH2

chlorobenzene aniline

Scheme 11

*

Br

When p-bromotoluene is treated with amide ion in liquid ammonia, 50:50 mixtures of p-

toludine and m-toludine is obtained (Scheme 12).

Br NH2

NaNH2

liq. NH3

CH3 CH3 CH3

NH2

p-bromotoluene p-toludine m-toludine

Scheme 12

From the above examples one can conclude that the reaction takes place by a

mechanism that forms an intermediate in which the two adjacent carbons are

equivalent. The experimental observations evidence the formation of a benzyne

intermediate where there is triple bond between the two adjacent carbons atoms of

benzene. In the first step of the mechanism, the strong base removes a proton

from the position ortho to the halogen. The resulting anion expels the halide ion,

thereby forming benzyne (Scheme 13).

Br

H

CH3

NH2

-Br-

CH3 CH3

carbanion benzyne

Scheme 13

NH2

NH2 NH2

The incoming nucleophile can attack either carbons of the “triple bond” of

benzyne (Scheme 14). Protonation of the resulting anion forms the substitution

product. The overall reaction is an elimination-addition reaction. Substitution at

the carbon that was attached to the leaving group is called direct substitution.

Substitution at the adjacent carbon is called cine (Greek: movement)

substitution.

NH2 NH2

H

CH3 CH3 CH3

p-toludine

H NH2

H

NH2

CH3 CH3 CH3

m-toludine

Scheme 14

H NH2

X

As halide leaves with its bonding electrons from the carbanion, an empty sp2

orbital remains that overlaps with the filled orbital adjacent to it, giving additional

bonding between these two carbon atoms. The two sp2 orbitals are directed 60°

away from each other, so their overlap is not very effective. Triple bonds are

usually linear but the triple bond in benzyne is a highly strained, so it is a very

reactive intermediate. Amide ion is a strong nucleophile, attacking at either end of

the benzyne triple bond. Subsequent protonation gives the product (Scheme 15).

Step 1: Deprotonation adjacent to the leaving group gives a carbanion

X

Nu-

H

Step 2: The carbanion expels the leaving group to give a "benzyne" intermediate.

Step 3: The nucleophile attacks at either end of the reactive benzyne triple bond.

Nu

Nu-

Step 4: Reprotonation gives the product

Nu Nu

H Nu H

Scheme 15

X

Benzyne is too unstable to be isolated but can be trapped by Diels-Alder reaction with

anthracene or furan. For example, Anthracene reacts with benzyne to give a symmetrical

cage structure (Scheme 16).

benzyne anthracene

Scheme 16

Reduction Catalytic hydrogenation of benzene to cyclohexane takes place at high temperatures and

pressures. Platinum, palladium, nickel, ruthenium or rhodium is used as catalyst. The

reduction cannot be stopped at an intermediate stage as these alkenes are reduced faster

than benzene (Scheme 17).

3 H2, pressure

Pt, Pd, or Ni

benzene cyclohexane

CH3 3 H2, pressure

CH3

CH3

Ru or Rh

CH3

m-xylene 1,3-dimethylcyclohexane

Scheme 17

Benzene and its derivatives can be reduced to nonconjugated cyclic dienes by treating

sodium or lithium liquid ammonia (Scheme 18). This reduction is called Birch

reduction.

Li, NH3 (l)

EtOH, Et2O

Scheme 18

A solution of sodium or lithium in liquid ammonia contains solvated electrons that can

add to benzene, forming a radical anion. The strongly basic radical anion abstracts a

proton from the alcohol, giving a cyclohexadienyl radical. The radical quickly adds

another solvated electron to form a cyclohexadienyl anion which is then protonated to

give the reduced product (Scheme 19).

Step 1: Formation of solvated electrons

NH3 Na or Li NH3 e- Na+

solvated electron

Step 2: Formation of a radical

H H

e-

H OR

H H

H

H H

radical

RO-

Step 3: Formation of the product

H H H H

e- H OR

RO-

H H H H H H

carbaion

Scheme 19