Chem 2124 unit 2c f2011

REACTIONS OF AROMATIC COMPOUNDS

Electrophilic Aromatic Substitution: The mechanism of many reactions of aromatic compounds are explained by minor variations of electrophilic aromatic substitution.

Recall that there are clouds of pi electrons above and below the sigma bonds of a benzene ring. These pi electrons are in a stable aromatic system. These pi electrons make the aromatic ring an electron rich materials. These pi electron are available to attach by strong electrophiles to give a carbocation intermediate.



Step 1: Attack on the electrophile forms the sigma complex.

Step 2: Loss of a proton gives the substitution product.


Show the mechanism for the following reaction.

+ Cl2 + AlCl

3

Hint: AlCL3 is a Lewis acid (an electron pair acceptor). Many substitution reactions involving an aromatic ring require a Lewis acid catalyst.



There are two things that must be considered when predicting the products of an electrophilic aromatic substitution reaction.

1. Identify the electrophilic species (what is the electrophile)?

2. What are the substituents groups that are already on the aromatic ring? (substituent effects)

REACTIONS OF AROMATIC COMPOUNDShalogenation

+ X2

Lewis acid

Lewis acids: AlX3 , FeX

3

X2 = Br

2 , CL

2

+ HX

X

REACTIONS OF AROMATIC COMPOUNDShalogenation

I2 + 2H+ + HNO3 2I

+ + NO2 + H2O

+ I+

H

Iodination requires an acidic oxidizing agent, like nitric acid, which oxidizes the iodine to an iodonium ion.

REACTIONS OF AROMATIC COMPOUNDSNitration

+ HNO3

H2SO4

+ H2O

NO2

The nitration of benzene is conveniently done using a mixture of nitric acid and sulfuric acid. The sulfuric acid is a catalyst which reacts with nitric acid to generate the nitronium ion (NO2

+). The use of sulfuric acid allows the reaction to take place at a faster rate and at a lower temperature.

85%

REACTIONS OF AROMATIC COMPOUNDSNitration

+ HNO3

H2SO4

+ H2O

NO2

Draw the mechanism for the nitration of benzene.


Zn, Sn, or Fe

HCl (aq)

NO2R R NH2

Reduction of nitroaromatics

Nitration of an aromatic ring is often the first step in a two step process that is used to add an amine group to an aromatic ring. The reduction of the nitro group is easily accomplished by treatment with a metal and dilute acid.

It is common in organic synthesis to add a functional group to a substrate and then to convert the group to the the desired group.

REACTIONS OF AROMATIC COMPOUNDSSulfonation of benzene

This reaction is done using fuming sulfuric acid (7% SO3 in H2SO4).

REACTIONS OF AROMATIC COMPOUNDSdesulfonation of benzene

Under what conditions do you think this reaction would be run?

REACTIONS OF AROMATIC COMPOUNDSExchange reactions of benzene

H

H

H

H

H

H

D

D

D

D

D

DD2SO4 / D2O

large excess

Write a mechanism for this reaction.

REACTIONS OF AROMATIC COMPOUNDSEffect of ring substituents

Mono-nitration of benzene gives only a single product, while mono-nitration of toluene can give three different products.

HNO3

H2SO4

o-nitrotoluene m-nitrotoluene

p-nitrotoluene(60%) (4%)

(36%)

CH3 CH3 CH3 CH3

NO2

NO2

NO2


There are two interesting observations that can be made when comparing the nitration of benzene vs toluene.

The first is that the reaction rate for toluene is ~25 times faster then benzene. The methyl group activated the ring toward electrophilic substitution. Methyl is an activating group.

The second is the distribution of products. If all of the positions on the ring were equivalent you would expect a 2:2:1 ratio of the ortho, metha and para products.


There are two ortho positions, two meta positions and one para position.

orthoortho

metameta

para

CH3


Nitration of toluene preferentially occurs at the positions ortho and para to the methyl group. The methyl group is referred to as being an ortho, para-director.

The presences of the methyl group on the aromatic ring has two effects. It affects reaction rates and where substitution occurs at on the ring.


You must be able to do the following:

1. Know how different functional groups are added to an aromatic ring.

2. Know how different substituent groups affect the reactivity of an aromatic ring.

3. Know how different substituent groups affect where substitution will occur.




The results seen here for toluene (methylbenzene) are general for all mono-alkylbenzenes when undergoing electrophilic aromatic substitution reactions.

The sigma complexes formed ortho and para to the alkyl group are more stable then the meta complex because the ortho and para complex have resonance forms with tertiary carbocations. This effect is called inductive stabilization because the alkyl group is donating electron density to the intermediate through the sigma bond.

REACTIONS OF AROMATIC COMPOUNDSEffect of substituents with non-bonding electrons

When a substituent group has a non-bonding pair of electrons on the atom directly bonded to the ring, the sigma complex initially formed during an electrophilic substitution reaction can be resonance stabilized by the non-bonding electrons.

+ E+ +

X: X:

E



The affect of resonance stabilization by substituents with non-bonding electrons on reaction rates can be very large. In the case of anisole the rate of nitration is ~10,000 time faster than benzene and ~ 400 times faster then toluene. This type of stabilization is also called resonance donating and pi-donating.

Substituents with non-bonding electrons are ortho/para directors. They may be either activating or deactivating.


Recall that the bromination of benzene required a Lewis catalyst. However, with strong activating substituent like the amino group in aniline the reaction occurs with multiply additions of bromine without a catalyst. Where did substitution occur at and what happens if you don’t have the bicarbonate in the reaction?


Activating Ortho/Para directors

REACTIONS OF AROMATIC COMPOUNDSDeactivating meta-directing substituents

We have seem how the presence of some substituents can greatly enhance the reactivity of an aromatic ring compared to benzene. We will now look at substituents that deactivate the aromatic ring toward electrophilic attack.

In electrophilic aromatic substitution reactions nitrobenzene is ~100,000 less reactive than benzene. In addition to deactivation of the ring the substitution occurs at the meta position.


In electrophilic aromatic substitution reactions nitrobenzene is ~100,000 less reactive than benzene. In addition to deactivation of the ring the substitution occurs at the meta position.

HNO3, 100 C

H2SO4

ortho (6%)meta (93%)

para (0.7%)

+ +

NO2 NO2 NO2NO2

NO2

NO2

NO2


Why does the nitro group deactivate the ring in electrophilic aromatic substitution reactions? Why is the nitro group a meta director?

To answer these questions we need to look at the intermediates that are formed during the reaction.






Structural characteristics of Meta-Directing Deactivators

1. The atom attached to the aromatic ring will have a formal positive charge or a partial positive charge.

2. Electron density is withdrawn inductively along the sigma bond, so the ring is less electron-rich than benzene. Destabilizes the sigma complex.



Halogenated aromaticsREACTIONS OF AROMATIC COMPOUNDS

Halogenated aromatic compounds under go electrophile substitution ortho and para to the halogen. This is an expected result since halogens have non-bonding electrons that can resonance stabilize the intermediate sigma complex .

Halogens are orhto/para directors but unlike other ortho/para directors, halogens deactivate the aromatic ring toward electrophilic substitution reactions. Why are halogens deactivators?`


Ortho and para attacks produce a bromonium ionand other resonance structures.


In the meta position there is no stabilization of the sigma complex.



Summary of substituent effects

What about multiple substituents?

When two or more substituents are present on an aromatic ring a combined effect is observed in subsequent reactions.

In many cases it is easy to predict the effects of multiple substituent groups because the individual effects are mutually supporting of each other.

In cases were there is a conflict in the directing effects of the substituent groups it can more difficult to predict what products will be produced.

REACTIONS OF AROMATIC COMPOUNDSEffects of multiple substituents

When dealing with multiple substituents activating groups are generally stronger directors than deactivating groups.

1. Strong activating ortho, para-directors that stabilize the transition state through resonance. i.e. –OH, –OR

2. Activating ortho, para-directors. i.e. alkyl groups and halogens

3. Deactivating meta directors.

REACTIONS OF AROMATIC COMPOUNDSEffects of multiple substituents

REACTIONS OF AROMATIC COMPOUNDSFriedel-Crafts Alkylation

What is the mechanism? Hint: Think about halogenation of an aromatic ring.

REACTIONS OF AROMATIC COMPOUNDSFriedel-Crafts Alkylation


Friedel-Crafts Alkylation



Rearrangement of the alkylating agent is possible and is limitation of Friedel-Crafts alkylation. As a result, only certain alkylbenzenes can be made using the Friedel-Crafts alkylation.



Multiple alkylation is a limitation and as a result mixtures of products are common.



Limitations of Friedel-Crafts Alkylation:

1. Only works with benzene and activated benzene derivatives. Fails with strong deactivating groups on the ring.

2. Rearrangement of the alkylating agent can occur, limiting the types of alkyl benzenes that can be produced.

3. Multiple alkylation's can occur resulting in undesired side products.

REACTIONS OF AROMATIC COMPOUNDSFriedel-Crafts Acylation

A deactivating group


Mechanism Friedel-Crafts Acylation

an electrophile species


Friedel-Crafts Acylation

1. The reaction require a full equivalent of Lewis acid, because the ketone product of the reaction will complex the Lewis acid.

2. The actual electrophilic species is thought to be a bulky complex, such as R-C+=O,AlCl4

-. As a result of the size of the electrophile, para substitution is predominate when the substrate contains an ortho/para

director.

3. The addition of the acyl group deactivates the ring toward additional substitution reactions.


Friedel-Crafts Alkylation vs Acylation

Alkylation:

Can not be used with strongly deactivated derivatives.

Carbocations involved in the

alkylation undergo rearrangement.

Multiply substitution is common.

Acylation:

Same

Acylium ions are not prone to rearrange.

Product is deactivated, limiting multiply substitutions.


Clemmensen Reduction

R

O

R

H H

Zn(Hg)

aq HCl


Cl

O

+

AlCl3

O

O

Zn(Hg)

HCl (aq)

Acylation followed by reduction.

REACTIONS OF AROMATIC COMPOUNDSGatterman-Kock Formylation

The above reaction allow for the formylation of aromatic compounds. The electrophile is the formyl cation [H-C+=O]. The insitu generation of the electrophile is required because formyl chloride (HCOCl) is unstable. See page 779.

CH2CH3

+ CO + HClCuCl

AlCl3

CH2CH3

O H


ClO

+

O

HNO3

H2SO4

???

?

O

H

?

?


Nucleophilic aromatic substitution

Nucleophilic substitution involves the attack of and electron rich group on the electron rich aromatic ring with subsequent lose of a leaving group and it’s electrons.

There are two mechanism that are seen with nucleophilic substitution reactions.

Addition-Elimination: requires strong electron withdrawing groups and a leaving group ortho or para to the electron withdrawing substituents.

Elimination-Addition: requires a good leaving group and the use of a very strong base or harsh reaction conditions(>200°C).





Nitro groups ortho and para to the halogen stabilize the intermediate (and the transition state leading to it). Without electron withdrawing groups in these positions, formation of the negatively charged sigma complex is unlikely.



F

NO2

NO2

H2N CH C

R

O

NH+ peptide

Sanger Reagent

?

6 M HCl / heat

?

Any thing interesting about the leaving group?


Elimination-addition mecchanism for Nucleophilic Aromatic Substitution

CH3

Br

CH3

NH2

CH3

NH2

+

NaNH2

NH3, -33°C

Notice that two products are produced from this reaction. The first is as expected with the bromine being replaced by an –NH2. The second product has the new substituent in an adjacent position.


Benzyne Mechanism for Nucleophilic Aromatic Substitution

The base that is used here is sodium amide (NaNH2).


Benzyne Mechanism for Nucleophilic Aromatic Substitution

What stereochemical issues are there with this mechanism?


Chlorination

There are eight isomer possible. The most important isomer is lindane, an insecticide.

+ 3 Cl2heat, pressure

or hv


Hydrogenation

The catalyst that are commonly used are Pt, Pd, Ni, Ru, or Rh.The temperature and pressure can vary considerably depending on the catalyst used.

+ 3 H2catalyst

1000 psig

100% cyclohexane


Burch Reduction



Reactions of side chains (oxidation with permanganate)

The alkyl groups on an aromatic ring can be converted to carboxylic acids by oxidation with permanganate or chromic acid.

CH2CH3 CO2HKMnO4, H2O or OH-

Heat

or Na2Cr2O7, H2SO4

If there are addition substituents on the ring they need to be resistant to oxidation. i.e. halo or nitro groups


Reactions of side chains (oxidation with permanganate)

CH3

CH3

CH3

CH3

Br


Reactions of side chains (halogenation)


Reactions of side chains (halogenation)

Benzylic halides are very reactive in both SN1 and SN2 reactions.

CHCH3

Br

CH3O-

CHCH3

Br

(CH3)3N

heat

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Chem 2124 unit 2c f2011