CHM 222 Chap 16: Electrophilic Aromatic Substitution

• Aromatic reactions are covered
• This chapter focuses on reactions involving benzene rings.

Electrophilic Aromatic Substitution

• Benzene primarily undergoes electrophilic aromatic substitution. This process maintains the aromaticity of the ring.
• During electrophilic aromatic substitution a hydrogen atom on the benzene ring is replaced by an electrophile.
• Reactions that keep the aromatic ring intact are favored where the aromatic ring is regenerated during the reaction.

Examples of Electrophilic Aromatic Substitution

• Halogenation replaces H with X (Cl or Br) using X₂ and FeX₃. The electrophile is Cl⁺ or Br⁺.
• Nitration replaces H with NO₂ using HNO₃ and H₂SO₄. The electrophile is NO₂⁺.
• Sulfonation replaces H with SO₃H using SO₃ and H₂SO₄. The electrophile is SO₃H⁺.
• Friedel-Crafts alkylation replaces H with R using RCl and AlCl₃. The electrophile is R⁺.
• Friedel-Crafts acylation replaces H with RCO using RCOCl and AlCl₃. The electrophile is R-C=O⁺.

Mechanism of Substitution

• All electrophilic aromatic substitution reactions proceed via a two-step mechanism:
• Addition of the electrophile E⁺ forms a resonance-stabilized carbocation.
• Deprotonation with a base.
• The first step forms a carbocation with three resonance structures, occurring only at ortho and para positions. Loss of a proton reforms the aromatic ring.

Halogenation

• In halogenation benzene reacts with X₂ to yield aryl halides with a Lewis acid catalyst.
• Chlorine, Cl₂, and bromine, Br₂, work effectively, however iodine, I₂, is unreactive, and fluorine, F₂, reacts too violently.
• Bromination involves a Lewis acid-base reaction of Br₂ with FeBr₃, creating a species with a weakened Br-Br bond. FeBr₄ removes a proton to reform the ring as the Lewis acid catalyst FeBr₃ is regenerated.
• Chlorination proceeds by a similar mechanism

Nitration and Sulfonation

• Nitration and sulfonation involve similar concepts.
• It is as if NO₂⁺ or HSO₃⁺ are added to the ring.
• Generation of the electrophile in these reactions requires a strong acid.

Friedel-Crafts Alkylation

• Treatment of benzene with an alkyl halide and a Lewis acid(AlCl₃) forms an alkyl benzene because a carbocation adds to the ring.
• This process introduces alkyl groups onto the benzene ring
• For CH₃Cl and 1° RCl, the electrophile forms a Lewis acid-base complex.
• For 2° and 3° RCl, a carbocation forms before acting as the electrophile.
• A carbocation electrophile forms a new carbon-carbon bond and AlCl₄ removes a proton for aromaticity.
• Any functional group capable of forming a carbocation can act as an electrophile with benzene.

Friedel-Crafts Acylation

• In Friedel-Crafts acylation, a benzene ring is treated with an acid chloride (RCOCl) and AlCl₃ to form a ketone.
• The reaction proceeds as if chlorine is substituted by the ring.
• Formation of the electrophile involves reaction is as if the chlorine has been substituted by the ring

Intramolecular Friedel-Crafts Reactions

• Starting materials contain both a benzene ring and an electrophile
• A new bond is formed

Directing Effects of Substituents

• Previous content covered unsubstituted benzene, but reaction outcomes change in the presence of substituents.
• Substituents affect the electron density of the ring by increasing or decreasing it, which affects reactivity. Electrophilic substitution on a substituted benzene produces isomers, where some are favored. These products are formed because of inductive and resonance effects or a combination of the two.
• Electron density affects where the electrophile will add to the ring and the most stable carbocation intermediate being formed.
• N, O, and X have an electron-withdrawing inductive effect, while alkyl groups have an electron-donating inductive effect.

Resonance Effects

• Resonance effects are common with substituents containing lone pairs or pi bonds.
• An electron-donating resonance effect occurs when resonance structures place a negative charge on carbons of the benzene ring.
• An electron-withdrawing resonance effect occurs when resonance structures place a positive charge on carbons of the benzene ring.

Alkyl Groups

• Alkyl groups donate electrons by an inductive effect, with no resonance effect due to the lack of nonbonded electron pairs or ㅠ bonds, any alkyl-substituted benzene is more electron rich than benzene itself.

Oxygen or Nitrogen Atoms

• O or N bonded directly to a benezene ring has a dominating resonance effect, which is electron donating
• An inductive withdrawing effect is present, but the resonance effect is stronger

Halogens

• When a halogen, X, is directly bonded to a benzene ring, then the inductive effect dominates and the net effect is electron withdrawal. X = Br, Cl, F, I.
• Any group with even a slight positive charge directly bonded to the ring has an inductive effect.

Substituent Effects Summary

• A substituent will affect the rate of the reaction. A substituted benzene can react faster or slower than benzene itself.
• The new group is located either ortho, meta, or para to the existing substituent because the identity of the first substituent determines the position of the second incoming substituent.

Directing Groups

• Electron-donating CH₃ groups activate the ring, making toluene react faster in all substitution reactions with ortho and para products predominating because an alkyl group is an ortho and para director.
• Electron-withdrawing NO₂ groups deactivate the ring which causes nitrobenzene reacting more slowly than benzene with a meta product predominating because the NO₂ group is called a meta director.

Types of Substituents

• Substituents that activate a benzene ring and direct substitution ortho and para including: -NH₂, -NHR, -NR₂, -OH, -OR, -NHCOR, -R
• All ortho, para directors are R groups or have a nonbonded electron pair on the atom bonded to the benzene ring.
• Substituents that deactivate a benzene ring and direct substitution ortho and para: -X (halogens)
• Substituents that direct substitution meta: -CHO, -COR, -CO₂R, -CO₂H, -CN, -SO₃H, -NO₂, -NR₃⁺
• All meta directors have a full or partial positive charge on the atom bonded to the benzene ring.
• Directing effects of a group on the ring are determined by the stability of the carbocation that forms after the electrophile adds to the ring, by using resonance and induction

Extra Concerning Activation Reactions

• A catalyst, FeX₃ is needed to add more than one halide, FeX₃, to benzene rings activated by strong electron-donating groups—OH, NH₂, and their derivatives OR, NHR, and NR₂ resulting in polyhalogenation
• Otherwise, only ortho and para products are formed by monosubstitution
• Monosubstitution of H by Br occurs with Br₂ alone without added catalyst to form a mixture of ortho and para products

Extra Concerning Deactivation Reactions

• Friedel-Crafts reactions will not occur on a benzene ring deactivated by strong electron-withdrawing groups, any of the meta directors
• Friedel-Crafts reactions will not occur on rings with NH₂ groups because AlCl₃ forms a complex with the NH₂ group that deactivates the ring

Additional Reactions

• An alkyl halide and AlCl₃ places an electron-donor R group on the ring which activates the ring for further reaction.
• Further Friedel-Crafts acylation reaction usually doesn't occur due to deactivating effects

Disubstituted Rings

• Having two substituents on a benzene ring results in each group having an influence on the results

Order of Addition

• Directing effects are used to synthesize disubstituted benzene products. Therefore the substituent must be added first to get a desired product.
• If bromination precedes nitration, then the desired product can be synthesized.
• If nitration occurs before bromination, then the undesired meta isomer is formed.

Nucleophilic Aromatic Substitution

• Nucleophilic aromatic substitution can also occur resulting in the substitution of a halogen on a benzene ring by a nucleophile with two different mechanisms being proposed.
• This substitution results in meta and para products, so the mechanism differs from electrophilic substitution.
• It occurs when there is an electron withdrawing group on the ring.

Questions cover Friedel-Crafts alkylation/acylation, halide reactivity, electrophiles, directing effects of substituents, and intramolecular reactions. Focus is on benzene's preference for substitution to maintain aromaticity and the electrophilic aromatic substitution mechanism.