Bromination of Benzene

Mechanism for the Bromination of Benzene: Preliminary Step

• Before the electrophilic aromatic substitution can take place, the electrophile must be activated.

• A strong Lewis acid catalyst, such as FeBr3, should be used.

Step 1: Electrophilic attack and formation of the sigma complex.

Step 2: Loss of a proton to give the products.

Mechanism for the Bromination of Benzene: Steps 1 and 2

Chlorination of Benzene

• Chlorination is similar to bromination. AlCl3 is most often used as catalyst, but FeCl3 will also work.

Nitration of Benzene

• Sulfuric acid acts as a catalyst, allowing the reaction to be faster and at lower temperatures.

• HNO3 and H2SO4 react together to form the electrophile of the reaction: nitronium ion (NO2

+).

Mechanism for the Nitration of Benzene: Preliminary Step

• Formation of the nitronium ion is the preliminary step of the reaction.

Mechanism for the EAS Nitration of Benzene

Step 1: Formation of the sigma complex.

Step 2: Loss of a proton gives nitrobenzene.

Friedel–Crafts Alkylation

• Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl3.

• Reactions of alkyl halide with Lewis acid produces a carbocation, which is the electrophile.

Mechanism of the Friedel–Crafts Reaction

Step 1

Step 2

Step 3

Rearrangements

Protonation of Alkenes

• An alkene can be protonated by HF. • This weak acid is preferred because the fluoride

ion is a weak nucleophile and will not attack the carbocation.

Alcohols and Lewis Acids

• Alcohols can be treated with BF3 to form the carbocation.

Limitations of Friedel–Crafts

• Reaction fails if benzene has a substituent that is more deactivating than halogens.

• Rearrangements are possible.• The alkylbenzene product is more reactive

than benzene, so polyalkylation occurs.

Friedel–Crafts Acylation

• Acyl chloride is used in place of alkyl chloride.• The product is a phenyl ketone that is less reactive

than benzene.

Mechanism of Acylation

Step 1: Formation of the acylium ion.

Step 2: Electrophilic attack to form the sigma complex.

Mechanism of Acylation (Continued)

Step 3: Loss of a proton to form the product.

The Gattermann-Koch Reaction

HINT

Friedel–Crafts acylations are generally free from rearrangements and multiple substitution. They do not go on strongly

deactivated rings, however.

Sulfonation of Benzene

• Sulfur trioxide (SO3) is the electrophile in the reaction.• A 7% mixture of SO3 and H2SO4 is commonly referred to as

“fuming sulfuric acid.”• The —SO3H group is called a sulfonic acid.

Sulfur Trioxide

• Sulfur trioxide is a strong electrophile, with three sulfonyl bonds drawing electron density away from the sulfur atom.

Desulfonation Reaction

• Sulfonation is reversible. • The sulfonic acid group may be removed from an

aromatic ring by heating in dilute sulfuric acid.

Nitration of Toluene

• Toluene reacts 25 times faster than benzene. • The methyl group is an activator.• The product mix contains mostly ortho and para

substituted molecules.

Ortho and Para Substitution

• Ortho and para attacks are preferred because their resonance structures include one tertiary carbocation.

Energy Diagram

Meta Substitution

• When substitution occurs at the meta position, the positive charge is not delocalized onto the tertiary carbon, and the methyl group has a smaller effect on the stability of the sigma complex.

Alkyl Group Stabilization

• Alkyl groups are activating substituents and ortho, para-directors.

• This effect is called the inductive effect because alkyl groups can donate electron density to the ring through the sigma bond, making them more active.

Anisole

• Anisole undergoes nitration about 10,000 times faster than benzene and about 400 times faster than toluene.

• This result seems curious because oxygen is a strongly electronegative group, yet it donates electron density to stabilize the transition state and the sigma complex.

Substituents with Nonbonding Electrons

Resonance stabilization is provided by a pi bond between the —OCH3 substituent and the ring.

Meta Attack on Anisole

• Resonance forms show that the methoxy group cannot stabilize the sigma complex in the meta substitution.

Bromination of Anisole

• A methoxy group is so strongly activating that anisole is quickly tribrominated without a catalyst.

Summary of Activators

Activators and Deactivators

• If the substituent on the ring is electron donating, the ortho and para positions will be activated.

• If the group is electron withdrawing, the ortho and para positions will be deactivated.

Nitration of Nitrobenzene

• Electrophilic substitution reactions for nitrobenzene are 100,000 times slower than for benzene.

• The product mix contains mostly the meta isomer, and only small amounts of the ortho and para isomers.

Ortho Substitution of Nitrobenzene

• The nitro group is a strongly deactivating group when considering its resonance forms. The nitrogen always has a formal positive charge.

• Ortho or para addition will create an especially unstable intermediate.

Meta Substitution on Nitrobenzene

• Meta substitution will not put the positive charge on the same carbon that bears the nitro group.

Energy Diagram

Deactivators and Meta-Directors

• Most electron-withdrawing groups are deactivators and meta-directors.

• The atom attached to the aromatic ring has a positive or partial positive charge.

• Electron density is withdrawn inductively along the sigma bond, so the ring has less electron density than benzene, and thus it will be slower to react.

Other Deactivators

Halogens

• Halogens are deactivators since they react slower than benzene.

• Halogens are ortho, para-directors because the halogen can stabilize the sigma complex.

Halogens Are Deactivators

• Inductive effect: Halogens are deactivating because they are electronegative and can withdraw electron density from the ring along the sigma bond.

Halogens Are Ortho, Para-Directors

• Resonance effect: The lone pairs on the halogen can be used to stabilize the sigma complex by resonance.

Energy Diagram

Summary of Directing Effects

Reduction of the Nitro Group

• Treatment with zinc, tin, or iron in dilute acid will reduce the nitro to an amino group.

• This is the best method for adding an amino group to the ring.

Clemmensen Reduction

• The Clemmensen reduction is a way to convert acylbenzenes to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc.

Wolff–Kishner Reduction

• Forms hydrazone, then heat with strong base like KOH or potassium tert-butoxide

• Use a high-boiling solvent: ethylene glycol, diethylene glycol, or DMSO.

• A molecule of nitrogen is lost in the last steps of the reaction.

Side-Chain Oxidation

• Alkylbenzenes are oxidized to benzoic acid by heating in basic KMnO4 or heating in Na2Cr2O7/H2SO4.

• The benzylic carbon will be oxidized to the carboxylic acid.

Side-Chain Halogenation

• The benzylic position is the most reactive.• Br2 reacts only at the benzylic position.

• Cl2 is not as selective as bromination, so results in mixtures.