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Chapter_17

Electrophilic Aromatic Substitution (EAS)

  • Benzene's pi electrons, though in a stable aromatic system, can attack strong electrophiles, forming a carbocation in the slow step.
  • This resonance-stabilized carbocation is termed a sigma complex, where the electrophile is sigma-bonded to the benzene ring.
  • Aromaticity is regained through the loss of a proton.

Mechanism of Electrophilic Aromatic Substitution

  • Step 1: Electrophile attack forms the sigma complex.
  • Step 2: Proton loss yields the substitution product.

Halogenation of Benzene

Bromination of Benzene

  • Requires activation of the electrophile with a strong Lewis acid catalyst like FeBr_3.
  • Reaction Equation:
    C6H6 + Br2 \xrightarrow{FeBr3} C6H5Br + HBr
  • \Delta H^\circ = -45 \text{ kJ/mol} \; (-10.8 \text{ kcal/mol})

Mechanism for Bromination of Benzene

  1. Preliminary Step: Activation of electrophile with Lewis acid catalyst, such as FeBr_3.
  2. Step 1: Electrophilic attack and sigma complex formation.
  3. Step 2: Deprotonation to yield products.

Energy Diagram for Bromination

  • Illustrates the energy changes during the reaction, highlighting the rate-limiting transition state and the intermediate sigma complex.

Chlorination of Benzene

  • Similar to bromination, but typically uses AlCl_3 as the catalyst

Iodination of Benzene

  • Requires an acidic oxidizing agent, such as nitric acid, to generate the iodide cation.

Nitration of Benzene

  • Sulfuric acid acts as a catalyst, enabling faster reactions at lower temperatures.
  • HNO3 and H2SO4 react to form the electrophile: the nitronium ion (NO2^+$).

Mechanism

  1. Preliminary Step: Formation of the nitronium ion.
  2. Step 1: Formation of the sigma complex.
  3. Step 2: Deprotonation to yield nitrobenzene.

Reduction of the Nitro Group

  • Treatment with zinc, tin, or iron in dilute acid reduces nitro to an amino group.
  • The best method for adding an amino group to the ring.

Sulfonation of Benzene

  • Sulfur trioxide (SO_3) is the electrophile.
  • A 7% mixture of SO3 and H2SO_4 is known as “fuming sulfuric acid.”
  • The —SO_3H group is called a sulfonic acid.

Mechanism of Sulfonation

  • Benzene attacks sulfur trioxide, forming a sigma complex.
  • Proton loss and reprotonation yield benzenesulfonic acid.

Desulfonation Reaction

  • Sulfonation is reversible.
  • The sulfonic acid group can be removed by heating in dilute sulfuric acid.

Mechanism of Desulfonation

  • A proton adds to the ring (the electrophile), and sulfur trioxide loss regenerates benzene.

Hydrogen–Deuterium Exchange

  • Confirmed using deuterium ion (D^+$) in place of a proton, showing deuterium incorporation in the product.

Nitration of Toluene: The Effect of Alkyl Substitution

  • 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

  • Preferred due to resonance structures including a tertiary carbocation.

Meta Substitution

  • The positive charge is not delocalized onto the tertiary carbon, so the methyl group has a smaller effect on sigma complex stability.

Activating, Ortho, Para-Directing Substituents

  • Alkyl groups are activating substituents and ortho, para-directors through the inductive effect.
  • They donate electron density to the ring, increasing activity.

Anisole

  • Undergoes nitration about 10,000 times faster than benzene and about 400 times faster than toluene.
  • Oxygen donates electron density, stabilizing the transition state and 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

  • Methoxy group cannot stabilize the sigma complex in meta substitution, as resonance forms show.

Bromination of Anisole

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

The Amino Group

  • Aniline reacts with bromine water (without a catalyst) to yield tribromoaniline.
  • Sodium bicarbonate is added to neutralize the HBr formed.

Summary of Activators

  • Includes phenoxides, anilines, phenols, phenyl ethers, anilides, and alkylbenzenes.

Deactivating, Meta-Directing Substituents

  • Electron-donating substituents activate the ortho and para positions.
  • Electron-withdrawing groups deactivate the ortho and para positions.

Nitration of Nitrobenzene

  • Reactions are 100,000 times slower than for benzene.
  • The product mix contains mostly the meta isomer, with small amounts of ortho and para isomers.

Ortho Substitution of Nitrobenzene

  • The nitro group is strongly deactivating due to resonance forms, with nitrogen always having a formal positive charge.
  • Ortho or para addition will create an especially unstable intermediate.

Meta Substitution on Nitrobenzene

  • Meta substitution will not place the positive charge on the carbon bearing the nitro group.

Para Substitution on Nitrobenzene

  • Para substitution will place the positive charge on the same carbon that bears the nitro group.

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, reducing ring electron density and reaction rate.

Ortho Attack of Acetophenone

  • In ortho and para substitution, a carbon atom bearing the positive charge is attached to the partial positive carbonyl carbon.
  • Repulsion between like charges makes this configuration unstable.

Meta Attack on Acetophenone

  • The meta attack avoids bearing the positive charge on the carbon attached to the partial positive carbonyl.

Other Deactivators

  • Includes nitro, sulfonic acid, cyano, ketone/aldehyde, ester, and quaternary ammonium ion groups.

Halogen Substituents: Deactivating, but Ortho, Para-Directing

  • Halogens are deactivators but ortho, para-directors.
  • They react slower than benzene, but the halogen can stabilize the sigma complex.

Halogens Are Deactivators

  • Inductive effect: Halogens are electronegative and withdraw electron density from the ring.

Halogens Are Ortho, Para-Directors

  • Resonance effect: Lone pairs on the halogen stabilize the sigma complex by resonance.

Summary of Directing Effects

  • Includes π Donors, σ Donors, Halogens, and Carbonyls.
  • Lists groups such as alkyl, halogens, hydroxyl, carbonyl, and nitro groups.
  • Classifies as ortho, para-directing (ACTIVATING) or meta-directing (DEACTIVATING).

Effects of Multiple Substituents on Electrophilic Aromatic Substitution

  • The directing effect of two (or more) groups may reinforce each other.
  • Positions between two groups in positions 1 and 3 are hindered and less reactive.
  • If directing effects oppose each other, the most powerful activating group has the dominant influence.

The Friedel–Crafts Alkylation

  • Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl_3.
  • Reactions of alkyl halide with Lewis acid produce a carbocation, which is the electrophile.

Mechanism

  1. Step 1: Formation of carbocation electrophile.
  2. Step 2: Electrophilic attack to form the sigma complex.
  3. Step 3: Deprotonation to regenerate the aromatic ring.

Protonation of Alkenes

  • An alkene can be protonated by HF; useful because the fluoride ion is a weak nucleophile.

Alcohols and Lewis Acids

  • Alcohols can be treated with BF_3 to form carbocations.

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.

Rearrangements

  • Ionization with rearrangement gives isopropyl cation.
  • Reaction with benzene gives isopropylbenzene.

The 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

  1. Step 1: Formation of the acylium ion.
  2. Step 2: Electrophilic attack to form the sigma complex.
  3. Step 3: Loss of a proton to form the product.

Clemmensen Reduction

  • A method to convert acylbenzenes to alkylbenzenes using aqueous HCl and amalgamated zinc.

Nucleophilic Aromatic Substitution

  • A nucleophile replaces a leaving group on the aromatic ring.
  • This is an addition–elimination reaction.
  • Electron-withdrawing substituents activate the ring for nucleophilic substitution.

Mechanism

  1. Step 1: Hydroxide attack gives a resonance-stabilized complex.
  2. Step 2: Chloride loss gives the product.
  3. Step 3: Excess base deprotonates the product.

Activated Positions

  • Nitro groups ortho and para to the halogen stabilize the intermediate.
  • Electron-withdrawing groups are essential for the reaction to occur.

Aromatic Substitutions Using Organometallic Reagents

  • Friedel-Crafts reactions have limitations (rearrangements, multiple alkylations, deactivated rings).
  • Organometallic reagents can add alkyl groups to the benzene without these limitations.

Organocuprate Reagents

  • Lithium dialkylcuprate reagents (Gilman reagents) are prepared by reaction of two equivalents of an organolithium reagent with cuprous iodide.
    (R = \text{alkyl, alkenyl, or aryl})

Coupling Using Organocuprate Reagents

  • Mechanisms vary depending on the alkyl halide and organocuprate used.
  • The stereochemistry of the vinyl halide is preserved.

The Heck Reaction

  • Palladium-catalyzed coupling of an aryl or vinyl halide with an alkene.
  • Produces C–C bond at the less substituted end of the alkene, usually with trans stereochemistry.
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