Reactions of Aromatic Compounds Study Notes

Organic Chemistry: Reactions of Aromatic Compounds

Author: Chad Snyder, PhD

### Source: Pearson Education, Inc.

Electrophilic Aromatic Substitution (EAS)

• Definition: A reaction where benzene’s pi electrons attack a strong electrophile, leading to the formation of a carbocation.

• Key Concept:

  • The carbocation formed is termed a sigma complex due to the new sigma bond created between the electrophile and the benzene ring.

  • Regaining aromaticity occurs through the loss of a proton.

Mechanism of Electrophilic Aromatic Substitution

1. Step 1: The electrophile attacks the benzene ring to form the sigma complex.

2. Step 2: The loss of a proton produces the substitution product.

Bromination of Benzene

• Reaction Overview:

  • Reagents: ________

  • Benzene reacts with bromine () in the presence of a catalyst, typically FeBr3.

• Reaction Enthalpy:

  • AH° for the reaction when producing bromobenzene:

  • +8 kJ (2 kcal) for the formation of the intermediate

  • -45 kJ (-10.8 kcal) for reaction completion

Mechanism of Bromination: Preliminary Step

• Activation: The electrophile must be activated. A strong Lewis acid, such as FeBr3, is essential.

Mechanism for Bromination Detailed Steps

1. Electrophilic attack forms the sigma complex.

2. Proton loss leads to the products.

Energy Diagram for Bromination

• Reactants: Benzene + Br₂ + FeBr₃

• Transition State: Rate-limiting

• Products: Bromobenzene + HBr + FeBr₃

• Change in enthalpy (ΔH): -45 kJ / mol

Chlorination of Benzene

• Similarities to Bromination:

  • Required Catalyst: AlCl3 or FeCl3

Iodination of Benzene

• Requirement for Reaction:

  • Needs an acidic oxidizing agent (e.g., nitric acid) to generate the iodide cation (I+).

  • Reaction Equation:
    $ext{H}^+ + ext{HNO}_3 + rac{1}{2} ext{I}_2 <br>ightarrow ext{I}^+ + ext{NO}_2 + ext{H}_2 ext{O}$

Nitration of Benzene

• Effects of Sulfuric Acid:

  • Acts as a catalyst making the reaction faster at lower temperatures.

• Formation of Nitronium Ion:

  • Created by the reaction of HNO3 and H2SO4.

  • Electrophile formed: NO2+.

Mechanism for Nitration of Benzene

1. Formation of the sigma complex from benzene and nitronium ion.

2. Loss of a proton results in nitrobenzene.

Reduction of the Nitro Group

• Reduction Process:

  • Using zinc, tin, or iron in dilute acid converts the nitro group to an amino group.

  • Preferred method to introduce an amino group into the aromatic ring.

Sulfonation of Benzene

• Electrophile: Sulfur trioxide (SO₃).

• Fuming Sulfuric Acid: A 7% mixture of SO₃ and H₂SO₄.

  • The resulting -SO₃H group is known as sulfonic acid.

Mechanism of Sulfonation

1. Benzene attacks SO₃ forming the sigma complex.

2. Loss of a proton and reprotonation yields benzenesulfonic acid.

Desulfonation Reaction

• Nature: Sulfonation is reversible.

• Method of Removal: Heating with dilute sulfuric acid can remove the sulfonic acid group from the aromatic ring.

Nitration of Toluene

• Reactivity: Toluene reacts 25 times faster than benzene.

• Activating Group: Methyl group directs electrophilic substitution primarily to ortho- and para-positions.

Ortho and Para Substitution

• Preference: Ortho and para attacks are favored as they result in resonance structures that include a tertiary carbocation.

Meta Substitution

• Comparison of Stabilization:

  • Meta substitution leads to less stability as the positive charge is not delocalized onto a tertiary carbon.

Alkyl Group Stabilization

• Effect: Alkyl groups function as activating substituents and direct substitution ortho and para.

  • Known as the inductive effect as alkyl groups donate electron density to the aromatic ring through the sigma bond, increasing reactivity.

Anisole and its Reactivity

• Reactivity: Anisole undergoes nitration approximately 10,000 times faster than benzene and about 400 times faster than toluene despite the electronegative oxygen group.

  • Reason: Oxygen donates electron density, stabilizing the transition state and sigma complex.

Substituents with Nonbonding Electrons

• Mechanism: The resonance form reveals that the -OCH₃ substituent stabilizes the sigma complex only at the ortho and para positions, not at meta.

Bromination of Anisole

• Reactivity: The methoxy group activates anisole so strongly that it undergoes tribromination without the need for a catalyst, assuming only a single reaction occurs.

Summary of Activators

Activators and Deactivators

• Activation: Electron-donating groups activate ortho and para positions.

• Deactivation: Electron-withdrawing groups deactivate those positions.

Nitration of Nitrobenzene

• Relative Speed: Nitrobenzene undergoes electrophilic substitution 100,000 times slower than benzene.

• Product Distribution: Main product is the meta isomer due to the effects of the nitro group.

Substitution Mechanism with Nitrobenzene

• Ortho Substitution: Generates an especially unstable intermediate due to the presence of the activating nitro group.

• Meta Substitution: Reduces the negative interaction between positive charges by avoiding overlap.

• Para Substitution: Results in instability as the positive charge overlaps with the nitro group.

Deactivators and Meta-Directors

• Types: Most electron-withdrawing groups are deactivators and direct substitution to meta.

• Effect: Inductive effects reduce electron density on the aromatic ring, making it less reactive.

Acetophenone Reactions

• Ortho vs. Meta: Ortho substitution is unstable due to charge interactions.

• Meta Attack: Avoids positive charge interactions ensuring stability.

Summary of Deactivators

Halogens as Substituents

• Properties: Halogens act as deactivators but are ortho, para-directors due to their resonance stabilization of the sigma complex.

  • Electron-withdrawing inductive effect dominates, slowing the reaction compared to benzene.

Summary of Directing Effects

Effect of Multiple Substituents

• Interactions: Directing effects can reinforce each other depending on their nature.

• Hindered Positioning: The position between two activators (1 and 3) is less reactive, while opposing effects yield the strongest activator dominating.

Friedel–Crafts Alkylation

• Procedure: Converts alkyl halides to alkylbenzenes in the presence of a Lewis acid like AlCl3.

Mechanism of Friedel-Crafts Reaction

1. Alkyl halide reacts with Lewis acid activating the formation of a carbocation.

2. Sigma complex formation occurs upon electrophilic attack.

3. Proton loss results in the alkylbenzene product.

Limitations of Friedel–Crafts

• Failure Condition: More deactivating substituents than halogens prevent their effective use.

• Rearrangement: Potential for carbocation rearrangement leading to mix products.

• Polyalkylation Issue: The product is more reactive than benzene, making it prone to further alkylation.

Friedel–Crafts Acylation

• Method: Employs acyl chlorides to produce phenyl ketones which are less reactive than benzene.

Clemmensen Reduction

• Definition: Converts acylbenzenes to alkylbenzenes via treatment with aqueous HCl and amalgamated zinc.

Nucleophilic Aromatic Substitution

• Mechanism: Involves a nucleophile replacing a leaving group through an addition-elimination mechanism.

• Activating Effect: Electron-withdrawing substituents enhance nucleophilic reactivity.

Mechanism of Nucleophilic Aromatic Substitution

1. Nucleophilic attack forms a resonance-stabilized complex.

2. Leaving group loss generates the final product.

3. The excess base deprotonates the product.

Aromatic Substitutions Using Organometallic Reagents

• Advantages: Bypass limitations of Friedel-Crafts, preventing rearrangements and multiple alkylations, and function effectively on deactivated rings.

Organocuprate Reagents

• Formation: Produced from reaction of two moles of an organolithium reagent with cuprous iodide.

• General Reaction:
  $ext{R-X} + 2 ext{Li} <br>ightarrow ext{R-Li} + ext{LiX}$
  $2 ext{R-Li} + ext{CuX} <br>ightarrow ext{R}_2 ext{CuX} + ext{LiX}$

Coupling Using Organocuprate Reagents

• Mechanisms vary by alkyl halide and organocuprate effectiveness.

• Not SN2: Works well with vinyl and aryl halides.

Side-Chain Oxidation

• Process: Alkylbenzenes oxidized to benzoic acid through heating with basic $ext{KMnO}_4$ or $ext{Na}_2 ext{Cr}_2 ext{O}_7/ ext{H}_2 ext{SO}_4$.

• Reactivity: The benzylic carbon is oxidized to a carboxylic acid.

Side-Chain Halogenation

• Reactivity: The benzylic position is the most reactive site.

• Bromination: Exclusively at the benzylic position.

• Chlorination: Results in mixtures due to reduced selectivity compared to bromination.

Mechanism of Side-Chain Halogenation

1. Formation of a resonance-stabilized benzylic radical.

2. Radical reactions with chlorine result in chlorinated products.

SN1 Reactions

• Benzylic carbocations are stabilized by resonance, making benzyl halides ideal for SN1 reactions.

SN2 Reactions

• Reactivity: Benzylic halides 100 times more reactive than primary halides for SN2 reactions due to ring stabilization in the transition state.

Examples of SN2 Reactions of Benzyl Halides

• Various halides undergo SN2 reactions as depicted in the context.