Substituição Eletrofílica Aromática – Parte 1 //// Mecanismos de Reações Orgânicas

Key Concepts

Substituição Eletrofílica Aromática (SEA): A type of reaction where an electrophile replaces a hydrogen atom on an aromatic ring.
Eletrófilo: An electron-deficient species that seeks electrons.
Íon Arênio (Íon de Guanidina): A carbocation intermediate formed during SEA reactions, stabilized by resonance.
Ácido de Lewis: A Lewis acid catalyst (e.g., AlCl₃, FeCl₃) used to activate electrophiles in SEA reactions.
Halogenação: SEA reaction involving halogens (e.g., Br₂, Cl₂).
Nitração: SEA reaction involving the nitro group (-NO₂).
Sulfonação: SEA reaction involving the sulfonic acid group (-SO₃H).
Alquilação de Friedel-Crafts: SEA reaction involving the introduction of an alkyl group.
Acilação de Friedel-Crafts: SEA reaction involving the introduction of an acyl group.
Íon Nitrônio (NO₂⁺): The electrophile in nitration.
Trióxido de Enxofre (SO₃): The electrophile in sulfonation.
Íon Acílio: The electrophile in acylation.
Íon Arênio: The resonance-stabilized carbocation intermediate in SEA.

General Aspects of Electrophilic Aromatic Substitution (EAS)

The video begins by contrasting the reactivity of alkenes with aromatic systems. Alkenes readily undergo electrophilic addition reactions, such as with HBr or Br₂, forming addition products. However, aromatic systems, like benzene, do not react under these usual conditions for electrophilic addition. Instead, they require specific conditions and undergo electrophilic aromatic substitution (EAS).

In EAS, an electrophile (E⁺) replaces a proton (H⁺) on the aromatic substrate. This process is generally a second-order reaction, with the rate depending on the concentrations of both the aromatic substrate and the electrophile, indicating a bimolecular rate-determining step.

Mechanism of EAS

The general mechanism for EAS involves two main steps:

Formation of the Arenium Ion: The aromatic system acts as a nucleophile, attacking the electrophile. This forms a resonance-stabilized carbocation intermediate known as the arenium ion (also called the sigma complex or Guanidine intermediate). In this step, the aromaticity of the ring is temporarily lost, making this the rate-determining step.
Regeneration of Aromaticity: A proton is eliminated from the carbon that bonded to the electrophile. This restores the aromaticity of the ring, forming the monosubstituted aromatic product.

The arenium ion is stabilized by resonance, with the positive charge delocalized across the ring. While a localized structure is convenient for drawing mechanisms, it's crucial to remember its resonance stabilization.

A potential energy diagram for EAS shows two transition states and an intermediate. The first transition state corresponds to the rate-determining step (formation of the arenium ion), and the second transition state corresponds to the deprotonation step. The arenium ion is less stable than the reactants due to the loss of aromaticity.

Formation of Electrophiles in EAS Reactions

The video then delves into the formation of specific electrophiles for various EAS reactions.

1. Halogenation

Reaction: Benzene reacts with a halogen (e.g., Br₂) in the presence of a Lewis acid catalyst (e.g., FeCl₃, AlCl₃, FeBr₃) to form a halobenzene.
Electrophile Formation: The halogen molecule (Br₂) coordinates with the Lewis acid (FeBr₃). This coordination polarizes the Br-Br bond, making one bromine atom more electrophilic. The second resonance structure shows a bromine atom with a formal positive charge, acting as the reactive electrophile.
Mechanism: The polarized Br₂ acts as the electrophile, attacking benzene to form the arenium ion. Subsequent deprotonation yields bromobenzene.

Experimental Evidence for the Arenium Ion

A crucial experiment demonstrated the existence of the arenium ion. Benzene was reacted with fluorosulfonic acid (FSO₃H) and antimony pentafluoride (SbF₅) at very low temperatures in sulfuryl chloride (SO₂ClF). This reaction formed an ion pair: the arenium ion and the hexafluoroantimonate anion ([SbF₆]⁻). The non-basic and non-nucleophilic nature of the counterion allowed the arenium ion to persist long enough to be detected by Nuclear Magnetic Resonance (NMR) spectroscopy.

NMR Data Comparison:
- Benzene: Shows a single signal for both ¹H NMR (7.33 ppm) and ¹³C NMR (129.7 ppm), indicating equivalent hydrogens and carbons.
- Arenium Ion: Exhibits distinct signals for different hydrogen and carbon environments:
  - Carbon/Hydrogen that received the electrophile (green): ¹H NMR at 5.6 ppm, ¹³C NMR at 52.2 ppm. The lower chemical shifts indicate sp³ hybridization, deviating from aromatic sp² hybridization.
  - Ortho positions (red): ¹H NMR at 9.7 ppm, ¹³C NMR at 186.6 ppm.
  - Meta positions (yellow): ¹H NMR at 8.6 ppm, ¹³C NMR at 136.9 ppm.
  - Para position (orange): ¹H NMR at 9.3 ppm, ¹³C NMR at 178.0 ppm.
- The higher chemical shifts for the arenium ion's hydrogens and carbons indicate a greater electron deficiency compared to benzene, as expected for a carbocation.
- Analysis of ¹³C NMR chemical shifts allowed calculation of the positive charge distribution: ortho and para positions bear a greater positive charge than the meta position. The charge distribution across the ortho and para positions corresponds to one-third of the formal positive charge on each, aligning with the three resonance structures of the arenium ion.

This experiment strongly supports the formation of the arenium ion as an intermediate in EAS reactions.

2. Nitration

Reaction: Benzene reacts with a mixture of concentrated nitric acid (HNO₃) and sulfuric acid (H₂SO₄) to form nitrobenzene.
Electrophile Formation: Sulfuric acid protonates the hydroxyl group of nitric acid, forming a protonated nitric acid species. The loss of a water molecule from this species generates the nitronium ion (NO₂⁺), which is the active electrophile.
Mechanism: The nitronium ion attacks benzene, forming the arenium ion, followed by deprotonation to yield nitrobenzene.

3. Sulfonation

Reaction: Benzene reacts with fuming sulfuric acid (oleum, a mixture of H₂SO₄ and SO₃) to produce benzenesulfonic acid.
Electrophile Formation: Sulfur trioxide (SO₃) is the reactive electrophile in this reaction.
Mechanism: SO₃ directly attacks benzene, forming the arenium ion, and subsequent deprotonation yields benzenesulfonic acid.
Reversibility: Sulfonation is a reversible reaction. In the presence of water and catalytic amounts of sulfuric acid, benzenesulfonic acid can be converted back to benzene. This reversibility can be utilized as a protecting group strategy in organic synthesis.

4. Friedel-Crafts Alkylation

Reaction: Benzene reacts with an alkyl halide (e.g., tert-butyl chloride) in the presence of a Lewis acid catalyst (e.g., AlCl₃) to introduce an alkyl group.
Electrophile Formation: The alkyl halide coordinates with the Lewis acid, forming a complex. This complex can then eliminate the Lewis acid's conjugate base (e.g., [AlCl₄]⁻) to generate a carbocation (e.g., tert-butyl carbocation).
Mechanism: The carbocation acts as the electrophile, attacking benzene to form the arenium ion. Deprotonation yields the alkylated benzene product (e.g., tert-butylbenzene).

Role of Lewis Acids in EAS

The necessity of Lewis acids in EAS, particularly in Friedel-Crafts reactions, is explained by the solvation properties of the reaction medium. EAS reactions often occur in non-polar solvents or with benzene itself as the solvent, which do not favor the formation of charged transition states. Lewis acids are crucial for activating the electrophile by coordinating with it, making it sufficiently electrophilic to react with the relatively weakly nucleophilic aromatic substrate and form the arenium ion.

Limitations of Friedel-Crafts Alkylation

Polyalkylation: It is common to obtain products with multiple alkyl groups substituted onto the benzene ring, as the alkylated product is often more reactive towards further EAS than benzene itself.
Rearrangements: Carbocations formed during the reaction can undergo rearrangements (e.g., hydride shifts) to form more stable carbocations. This leads to the formation of rearranged products, often in significant amounts. The reaction of an alkyl halide with a Lewis acid can lead to the formation of a more stable carbocation through rearrangement before attacking the aromatic ring.

5. Friedel-Crafts Acylation

Reaction: Benzene reacts with an acyl halide (usually an acyl chloride) or an acid anhydride in the presence of a Lewis acid catalyst to introduce an acyl group.
Electrophile Formation: The acyl halide (e.g., acetyl chloride) coordinates with the Lewis acid (e.g., AlCl₃). The non-bonding electrons of the carbonyl oxygen are involved in the coordination, and the departure of the Lewis acid's conjugate base leads to the formation of the acylium ion (R-C=O⁺). This ion is a highly electrophilic species with a positive charge on the oxygen.
Mechanism: The acylium ion attacks benzene, forming the arenium ion. Deprotonation yields an aromatic ketone.
Water Addition: Water is added in a second step to hydrolyze the complex formed between the Lewis acid and the ketone product, liberating the pure ketone. This is necessary because the ketone product can also coordinate with the Lewis acid, deactivating it.
Stoichiometry of Lewis Acid: More than one equivalent of Lewis acid is typically required because one equivalent is consumed in catalyzing the formation of the acylium ion, and another equivalent coordinates with the ketone product. Using excess Lewis acid improves yields.

Strategic Use of Friedel-Crafts Acylation

Friedel-Crafts acylation is often preferred over alkylation for synthesizing monoalkylated aromatic compounds. This is because:

No Polyacylation: The acyl group is deactivating, preventing further EAS reactions on the product.
No Rearrangements: The acylium ion does not undergo rearrangements.

The aromatic ketone product can then be converted to a monoalkylated benzene through a two-step process: reduction of the carbonyl group to a methylene group (e.g., using Wolff-Kishner or Clemmensen reduction) followed by conversion to a benzyl halide and then reaction with a reducing agent like LiAlH₄.

Conclusion

The video concludes by summarizing the key EAS reactions discussed: halogenation, nitration, sulfonation, Friedel-Crafts alkylation, and Friedel-Crafts acylation. It highlights the specific electrophiles involved in each reaction and the crucial role of Lewis acids in activating electrophiles, particularly in Friedel-Crafts reactions. The discussion on the arenium ion intermediate and the experimental evidence supporting its existence is also emphasized. The next video will focus on the reactivity of substituted benzene derivatives in EAS reactions.