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

No reaction if any of these groups are on the ring.

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

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