Organic Lecture 2/21

Mechanisms of Electrophilic Aromatic Substitution: Halogen

• The process begins with a bromine and a bromine cation (Br+), which can arise from the collapse of an iron pair in a reaction mixture.

• The benzene ring acts as a nucleophile, exhibiting the ability to attack electrophiles such as Br+.

• Formation of the addition product results in the loss of stabilization of the aromatic ring. Formation of substitution product regenerates the resonance-stabilized aromatic ring.

• Iodine: Use nitric acid for its reaction

Nitration of Arenes

• Benzene reacts with nitric acid in the presence of H2SO4/30-40Celsius, creates a nitrobenzene with water as a side product. Nitration gives very high yields.

• Tyrosine: An amino acid that contains a phenolic hydroxyl group. Its structure includes a benzene ring off the side chain, making it susceptible to nitration.

• Using nitric acid on tyrosine can lead to nitration, where the hydroxy group can influence reactivity.

• During this reaction, the negatively charged oxygen does pick a proton, but this step does not lead to product formation.

• Nitronium ion acts as the electrophile in nitration of arenes.

• Water is the base of the reaction.

Sulfonation of Arenes

• Mixing red powder (likely sulfur trioxide) with sulfuric acid yields fuming sulfuric acid, which releases toxic SO2 gas.

• Reaction: Benzene + SO3 in the presence of H2SO4 adds SO3 to benzene (benzenesulfonic acid)

• Generate electrophile (HSO3+), benzene attacks electrophile to form carbocation, then regenerate aromaticity. The base is either HSO4- or another molecule of the HSO3.

• This reaction is the only electrophilic addition to the aromatic ring that is reversible: heating with water can reverse these reactions. Low heat adds ortho; high heat adds para.

Influence of Substituents on the Aromatic Ring

• The benzene ring’s role as a nucleophile means substituents can influence its reactivity.

• Electron-Withdrawing Groups (EWGs): These reduce nucleophilicity by pulling electron density away from the ring, making it less likely to undergo electrophilic substitution.

• Electron-Donating Groups (EDGs): Conversely, groups like alkyl chains can donate electrons via hyperconjugation, increasing the reactivity of the ring.

• Example: A methyl group (–CH3) added to benzene increases its electron density, hence it reacts quicker with additional electrophiles compared to benzene alone.

Friedel-Crafts Alkylation Reactions

• Friedel-Crafts alkylation and acylation can add alkyl groups to the aromatic ring. Alkylation introduces a methyl group, which then facilitates further reactions.

• If one benzene has a methyl group, it reacts quicker than another benzene without a methyl group due to already increased electron density.

• no vinyl halides

• can go through carbocation rearrangements

• reaction fails if the electron-withdrawing group is attached to the ring because aromatic ring acts as the nucleophile

• Hard to stop at just one alkylation

Friedel-Crafts Acylation

• Chlorine attacks aluminum. This leads to the formation of an acylium ion, which then reacts with the aromatic compound to introduce an acyl group.

• Multiple additions not probable because electron withdrawing group is attached to the ring. Acyl ions are easily formed and can be made from acid anhydrides as well.

• An alternative for introducing alkyl groups involves converting bromine into a Grignard reagent to perform an SN2 attack on a primary halide.

• This is often followed by reduction using hydrazine (N2H4) solvated in basic triethylene glycol (representing a solvent with particular boiling point conditions).

Clemmensen Reduction

• Reduction of carbonyls. Does not reduce carboxylic acids or interfere with alkenes/alkynes

Wolff-Kishner Reduction

• This reduction process is essential for turning acylated products into alkylated products, crucial for aromatic compound modifications.

• Does not reduce carboxylic acids or interfere with alkenes/alkynes

• The selection of triethylene glycol, with a higher boiling point (around 75 °C), is key for energy-demanding reactions to ensure proper conditions.

• method of choice most of the time