AROMATIC SUBSTITUTIONAROMATIC SUBSTITUTION

REACTIONS REACTIONS

� Electrophilic

� Nucleophilic

Benzene undergoes substitution reactions instead of addition.It requires a strong electrophile

Cl2

FeCl3

Cl

ClH+ +

Benzene ReactivityBenzene Reactivity

Substitution

Cl2

Cl

Cl+

compare:

addition

Substitution….

Why??

How??

Influence of preexisting groups

Synthetic utility

+ Br2

Br

H

H

Br-

---------------------------------------------------------------------------

∆H

-27 kcal/mol

Br

H

HBr-

Br

Br

Br

+ HBr

-11 kcal/mol

Addition Substitution

Energy profile in the case of Olefins – Addition vs. Substitution

∆H

Addition Substitution

----------------

----------------

----------------

+9 kcal/mol-11 kcal/mol

+ Br2

Br

+ HBr

BrH

Br HBr

Br

BrH

Br-Br

H

Br-

AlCl3

Energy profile in the case of Benzene – Addition vs. Substitution

----------------

General reaction:

+ E B

H E

+ B

H E H E

Step 1:

a stabilized cyclohexadienyl cation

(also called a benzenonium ion)

Step 2:

H E

+ B

E

+ H-B

How???

Energy profile of aromatic substitution reactionEnergy profile of aromatic substitution reaction

H

E

E

+

Ea

H+

benzenonium

intermediateTransition

state 1

Transition

state 2

STEP 1 STEP 2

slowfast

activation

energy

intermediate

H E

The absence of

Kinetic isotope effect

shows that the second step

(that involves TS2) is not

Rate Determining

Substitution Reactions of BenzeneSubstitution Reactions of Benzene

Cl2

AlCl3

Cl

CH3Cl

AlCl3

CH3

CH3

CCl

O AlCl3

C CH3

O

OH N

O

O

H2SO

4

N O

O

S

O

OH

OOH S

O

O

OHSO

3

+

+

+

+

+

Halogenation

Friedel-Crafts

Alkylation

Friedel-Crafts

Acylation

Nitration

Sulfonation

+ +

-

-

Chlorination of BenzeneChlorination of Benzene

H

Cl

Cl

Cl

AlCl4

AlCl4

+ -

-

HCl + AlCl3

chloronium

ion complex

[ ] +Benzenonium ion

Cl2 + AlCl3

FriedelFriedel--Crafts AlkylationCrafts Alkylation

H

CH3

CH3

CH3

AlCl4

AlCl4

+ -[ ] +

CH3Cl + AlCl3

HCl + AlCl3

-

Consider all resonance

contributors

alkylation of benzene by alcohol

FC alkylations can give problems due to rearrangement FC alkylations can give problems due to rearrangement

of carbocations to more stable onesof carbocations to more stable ones

FriedelFriedel--Crafts AcylationCrafts Acylation

H

C CH3

O

C

O

CH3

C

O

CH3

AlCl4

AlCl4

+ -[ ] +

+ AlCl3

HCl + AlCl3

CH3

C

O

Cl

-

Since AlCl3 complexes with C=O group,

2 eq. of this reagent is required

C

O

CH2CH

3

C

O

CH3CH

2Cl

AlCl3

CH2CH

2CH

3

CH3CH

2CH

2Cl

AlCl3

Zn / HCl

X

Rearrangement is a

problem

AcylationAcylation followed by followed by ReductionReduction is a convenient routeis a convenient route

to introduce long alkyl chains on aromatic ring; Noto introduce long alkyl chains on aromatic ring; No

problem of rearrangement problem of rearrangement !!

Clemmensons reduction

Alkylation of Benzene by AcylationAlkylation of Benzene by Acylation--ReductionReduction

Advantages :

(1) No rearrangement

(2) No multiple substitutions (acyl- group is de-activating)

Nitration of BenzeneNitration of Benzene

pKa = -5

pKa = -1.3

(consider all resonance forms)

Sulfonation of BenzeneSulfonation of Benzene

Concentrated

or Fuming

H2SO4.SO3

(Fuming sulfuric acid)

also can be used

(Consider all resonance forms)

Sulfonation of BenzeneSulfonation of Benzene

O

S

O

OH

H

S OH

O

O

S

O

OH

O

HSO4

+

-

H2SO4 SO3.

+ H2SO4

can be

reversed

in boiling water

or steam (acidic)

H3O+

∆∆∆∆

Look.. It is reversible

CH3CH3

D

?

How would you do the following

conversion

Energy profile in Sulfonation

Depending upon whether they are electron

donating or electron withdrawing,

substituents fall into one of the following

categories:

o,p - directors m- directors

activate the ring deactivate the ring

Substitution categoriesSubstitution categories

G

Ripso

ortho

meta

para

o-

m-

p-

1

2

3

4

5

6

Directing effect of groups,Directing effect of groups,ring activation and deactivationring activation and deactivation

O CH3

Example, Nitration of AnisoleExample, Nitration of Anisole

NO2

O CH3

NO2

O CH3

Reacts faster

than benzene

+

ortho para

= “activated”

The -OCH3 (or other electron donating groups) if present on the ring,

give preferentially ortho and para products, and no meta.

Substituents that cause this effect are called o,p directors

HNO3

H2SO4

anisole

ACTIVATED RING

and they usually activate the ring

C

OOMe

Example Nitration of Methyl BenzoateExample Nitration of Methyl Benzoate

CO

NO2

OMe

Reacts slower

than benzene

meta

HNO3

H2SO4

= “deactivated”

methyl benzoate

The -COOMe (or other electron withdrawing groups) if present

on the ring give only meta, and no ortho or para products.

Substituents that cause this result are called m directors

and they usually deactivate the ring.

DEACTIVATED RING

H

HNO

2

O CH3

+

H

H

NO2

O CH3

+

H NO2

H

O CH3

+

O CH3

+ N

O

O

+

Nitration of AnisoleNitration of Anisole

NO2

O CH3

NO2

O CH3

actual

products

Activated ringortho meta para

ortho para+

Benzenonium ion-resonance forms

H NO2

H

O CH3

+

H NO2

H

O CH3

+

H NO2

H

O CH3

+

H NO2

H

O CH3

+

H

H

NO2

O CH3

+

H

H

NO2

O CH3

+

H

H

NO2

O CH3

+H

H

NO2

O CH3

+

H

HNO

2

O CH3

+

H

HNO

2

O CH3

+

H

HNO

2

O CH3

+

ortho

meta

para :

:

Extra stabilization and extra resonance structure

Extra stabilization and extra resonance structure

H

H

C

O

NO2

OMe

+

H

C

O

H

OMe

NO2

+

C

OOMe

H NO2

H

+

CO

OMe

+ N

O

O

+

Nitration of Methyl BenzoateNitration of Methyl Benzoate

CO

NO2

OMe

actual

product

Deactivated ring ortho meta para

meta

Benzenonium ion-resonance forms

H

H

CO

NO2

OMe

+

H

H

C

O

NO2

OMe

+

H

H

C

O

NO2

OMe

+

ortho

meta

para

H

C

O

H

OMe

NO2

+

H

C

O

H

OMe

NO2

+

H

C

O

H

OMe

NO2

+

δ+δ+δ+δ+δδδδ−−−−

δ+δ+δ+δ+δδδδ−−−−

C

OOMe

H NO2

H

+

C

OOMe

H NO2

H

+

CO

OMe

H NO2

H

+

BAD!

BAD!

• Classification of Substitutents

Deactivators (m-directing)

Comparison of Activators and deactivatorsRelative energy states of intermediates with respect to that of benzene

Benzene

Activators (o/p directing)E

+

orthoortho, , parapara -- Directing GroupsDirecting Groups

X

Groups that donate

electron density

to the ring.XX :

+I Substituent +R Substituent

CH3-

R-

CH3-O-

CH3-N-

-NH2

-O-H

These groups

“activate” the ring, or

make it more reactive.

E+

The +R groups activate

the ring more strongly

than +I groups.

..

..

..

..

..

..

increased

reactivity

PROFILE:

X YY

metameta -- Directing GroupsDirecting Groups

X

Groups that withdraw

electron density from

the ring.

These groups

“deactivate” the ring,

or make it less reactive.

E+

-I Substituent -R Substituent

δ+δ+δ+δ+ δδδδ−−−−

C

O

R

C

O

OR

C

O

OH

C N

N

O

O

N

R

R

R

CCl3

-SO3H

+

decreased

reactivity

+

-

PROFILE:

Halides Halides -- o,po,p Directors / Deactivating;Directors / Deactivating;an exception to the trend we saw in the previous slidean exception to the trend we saw in the previous slide

X

E+

: :..

Halides represent a special case:

They are o,p directors (+M effect )

They are deactivating ( -I effect )

-F

-Cl

-Br

-I

X =

OH OH

Br?

How would you bring about the following conversion efficiently?

Directing effect of groups: Application in synthesisDirecting effect of groups: Application in synthesis

NO2

NO2

Br

NO2

Br

NO2

How would you bring about the following conversions efficiently?

Br

CH2CH2CH3

CH3CH2 C

O

Cl

AlCl3

CO CH2CH3

Br2

FeBr3

CO CH2CH3

Br

CH2

CH2CH3

Br

Zn(Hg)HCl??

Br

Cl CH2CH2CH2CH2 ClAlCl3

junk!!

X

Cl CH2CH2CH2C OH

O

AlCl3

CH2CH2CH2C OH

O

SOCl2

CH2CH2CH2C Cl

O

O

AlCl3

HCl

Zn(Hg)

α-tetralone

You can also consider a route

through succinic anhydride

(draw the sequence)

?

Ref: Syn. Commun.,Vol. 34, No. 12, pp. 2301–2308, 2004

NH2 NH2

Cl

NH2 NH2

NO2

??

Example

??

NH2 NH2

SO

O

HN

R

Sulfa drugs (very important class of

Antibacterials)

Clue: steps in random order

chlorosulfonation, amination, N-acetylation, de-acetylation

Give reasons for N-acetylation????

?

COOH

CH3

COOH

COOH

NO2

NO2O2N

??

????

General rulesGeneral rules

1) Activating (o,p) groups (+R, +I) win over

deactivating (m) groups (-R,-I)

2) Resonance groups (+R) win over inductive (+I) groups

3) 1,2,3-Trisubstituted products rarely form due to

steric crowding

4) With bulky directing groups, there will usually be more

p-substitution than o-substitution

5) The incoming group replaces a hydrogen, it will not

usually displace a substituent already in place (in the case of

electrophilic aromatic substitution)

Directing effect if more than one substituent is presentDirecting effect if more than one substituent is present

Case 1. When two substituents direct to the same positionCase 1. When two substituents direct to the same position

O CH3

NO2

m-director

o,p director

HNO3

H2SO4

O CH3

NO2

NO2

major

product

CH3

NO2

NO2+

CH3

NO2

NO2

99.8%

CH3

NO2

0.2%

Why a mixture

in this case ??

(assuming 1:1)

o,p-directing groups win

over m-directing groups

HNO3

H2SO4

O CH3

NO2

NO2

O CH3

NO2

O2N

O CH3

NO2

Steric

crowding

+

Activation effect of o,p directors are stronger than the meta directing deactivators.

Case 2. When two substituents direct to the different positions Case 2. When two substituents direct to the different positions

(activation vs. deactivation)(activation vs. deactivation)

X

HNO3

H2SO4

O CH3

CH3

NO2

O CH3

CH3

+R

+I

resonance effects are more

important than inductive effects

major

product

Case 3. Resonance vs. inducting effectCase 3. Resonance vs. inducting effect

The alkyl groups and halides are in-between (mixture of products)

Steric and electronic effects can decide the outcome

O

O

??

Problem

Electrophile

Ar-NH2 ArN2+

A different electrophile

Show how ArN2+ is formed

There are two resonance structures which retain fully conjugated aromatic ring

in the case of substitution at position 1.

Naphthalene- electrophilic substitution

Electrophilic substitution of Naphthalene

H

Peri interaction

Allura Red

A red azo dye, used in many food, drug and cosmetic products

Synthesis of Shaffer acid required for the synthesis of Allura red

Method: Sulfonate 2-naphthol twice (ie. 1,6-disulfonate) and then desulfonate once.

Why desulfonation happens only at position 1?

SO3H

OH

HO3S

12

6

HO3S

O

HO3S

12

6

H

H

Consider other resonance forms also

OH

HO3S

22

6

+SO3HH2O

-H+H2SO4

2-hydroxynaphthalene-6-sulfonic acid (shaffer acid)

(irreversible

in dil H2SO4)

(First Sulfonation of 2-naphthol

goes to position 1 and the second goes to

position 2; First desulfonation happens at position1)

Neither true SN1 or SN2 is energetically feasible in

aromatic Systems

1. pi electrons in conjugation

2. Back side attack (as in SN2) and inversion is precluded by the

geometry of the ring

1. SN1 leads to phenyl cation which is less stable than a primary carbocation

Two types of mechanisms that operate in Nucleophilic substitutions are,

1. Addition-Elimination

2. Elimination-Addition

Nucleophilic Aromatic Substitution

X

Nu

X

Nu

Nu + X-

Nu X

1. Addition-Elimination (SNAr)

Groups which favor substitution

NO2, CN, -CO-

The formation of the addition intermediate is usually the RDS

For halogens, the order of reactivity is F > Cl > Br> I(stronger bond dipoles associated with the more electronegative atom favor the

addition step)

Meisenheimer complex

EWGEWG

EWG

leaving groups Halogens, Alkoxy, NO2, Sulfonyl

Examples

Nucleophiles in aromatic substitution

Alkoxides, Phenoxides, Sulfides, fluoride ion or amines

(similar to that in SN2)

The rate of the reaction gets enhanced on using

Dipolar aprotic solvents, crown ethers or other phase transfer catalysts

(by providing the nucleophile in a reactive state with minimum solvation)

Cl

+ OH-< 300oC

No reaction

Electron withdrawing groups stabilize Meisenheimer complex and favor the reaction

Energy profile

Which among these

Substrates undergo

the reaction efficientlyWhich chloride will

be nucleophilically

Substituted?H3C

Cl

CH3

Cl

NO2O2N

Cl

NO2

NO2

Cl

Meisenheimer complex

It is possible to isolate the Meisenheimer complex in some cases! Stable!

O2N

NO2

F

OHNO

R1

H2N R2

OHNO

R1

HN

R2O2N

NO2

+

O

R1

HNO2N

NO2

OH

HYDROLYSIS

Sanger’s Method of N-terminal Amino acid determination in proteins

One important application of nucleophilic aromatic substitution reaction

�The 2,4-dinitrofluorobenxene (2,4-DNP)

is treated with the protein of interest

under mild alkaline conditions (doesn't

cause cleavage of peptide bonds)

�The DNP-protein adduct is then

subjected to acid hydrolysis which lead

to the cleavage of peptide bonds,

leaving the N-terminal residue in the

form of its DNP-derivative

�This derivative can be identified by

chromatographic methods

Elimination-Addition (Benzyne mechanism)

14C

14C14C

14C

‘Cine’ Mechanism- evidence

What is the electrophilic species generated from HNO2/H2SO4 ?

Some functional group

Inter-conversions you can

consider while writing

a sequence

S

NH

O

OO

Br

NO2

SO3

H2SO4

NO2

O2N

How would you make this compound

Predict the product

Predict the product

Which among these products are most likely to be formed?

Answer by analyzing resonance structures of intermediates

O

HN

H2SO4

HNO3

H2SO4

HNO3

H2SO4

HNO3

How??

NHAc

Cl

O

Cl+

What is the product if 1 eq. of AlCl3 is used

Which is kinetic and which

is thermodynamic product?