Chapter 16

CHAPTER 16 Electrophilic Attack on Derivatives of Benzene: Substituents Control Regioselectivity

EAS - Substituent and Regioselectivity

• Substituents on benzene can be categorized into two main groups:

  • Activators (Electron donors)

    • Direct a second electrophilic attack to the ortho and para positions.

  • Deactivators (Electron acceptors)

    • Direct a second electrophilic attack to the meta positions.

Activation or Deactivation by Substituents

• The electronic influence of substituents is determined by two main factors:

  • Inductive Effect

    • Occurs through the sigma (s) framework.

    • Strength diminishes rapidly with distance and primarily relates to the electronegativity of the atoms.

  • Resonance Effect

    • Occurs through pi (p) bonds.

    • Has a longer range and is particularly strong in charged systems.

Inductive Donors and Acceptors

• Electron-Donating Groups:

  • Simple alkyl groups primarily act as donors due to hyperconjugation.

• Electron-Withdrawing Groups:

  • CF3 group (trifluoromethyl) is electron-withdrawing due to electronegative fluorine atoms.

  • Directly bound heteroatoms (N, O, halogens) withdraw electrons due to their electronegativities.

  • Groups like carbonyl, cyano, nitro, and sulfonyl are also electron-withdrawing.

Resonance Effect with the Ring

• Groups like –NR2, –OR, and halogens act as resonance donors.

• The opposing influences of inductive and resonance effects depend on relative electronegativity and the ability of p-orbitals to overlap.

  • Resonance prevails for amino and alkoxy groups.

  • Inductive effects dominate for halogens, rendering them weak electron acceptors.

Reinforcement of Induction and Resonance

• Groups like carbonyl, cyano, nitro, and sulfonyl are also electron-withdrawing through resonance, where their positively polarized ends attach to the benzene nucleus, reinforcing induction.

Effect of Electron-Donating and Withdrawing Groups

• Electron-Donating Groups:

  • Increase electron density in the benzene ring.

• Electron-Withdrawing Groups:

  • Decrease electron density in the benzene ring.

• Reactivity: The more electron-rich the arene, the faster the reaction.

Directing Inductive Effects of Alkyl Groups

• Alkyl groups that donate electrons by induction activate and direct to ortho and para positions, with minimal meta product formation.

Reaction Outcomes: Nitration, Sulfonation, Friedel-Crafts

• Methylbenzene shows regioselectivity for ortho and para substitutions, regardless of the reagent used due to the methyl group being an activating and ortho-para directing substituent.

Transition States in Regioselectivity

• Both ortho and para attacks offer transition states that are stabilized by resonance forms showing a positive charge on a tertiary carbon atom, unlike meta, where charge is on a less stable secondary carbon.

• Steric effects often lead to para products predominating over ortho isomers.

Deactivating and Meta-directing Groups

• Groups that withdraw electrons (e.g., trifluoromethyl) deactivate the benzene ring, slowing reactions and primarily yielding meta-position products.

Transition State Stability

• Ortho and para attacks result in less stable transition states compared to meta because of charge proximity to electron-withdrawing groups; meta offers a more stable transition state.

Activating and Directing Effects by Resonance Groups

• Groups like –NH2 and –OH strongly activate the ring and lead to exclusive ortho and para substitutions.

Modifying Substituents for Better Control

• Adjusting amino and hydroxy substituents provides better control over the direction of substitutions.

• Examples: N-phenylacetamide and methoxybenzene are less strongly activating but still direct ortho and para.

Activation and Regioselectivity with Amino Group

• The resonance forms for the cation intermediates show stabilization in ortho or para transition states, contributing to the lack of meta product formation.

Electron Withdrawal by Resonance and Meta Directing Groups

• Groups like the carboxy group deactivate the benzene ring and favor meta substitution due to lower reaction rates compared to unsubstituted benzene, demonstrating meta-directing behavior.

Halogen Substituents: An Exception

• Halogens are unique: they are deactivating yet direct ortho and para positions due to their ability to donate electrons through resonance while withdrawing inductively.

Competition Between Induction and Resonance

• In ortho and para positions, resonance delocalizes the positive charge, outweighing the halogen's electron-withdrawing inductive effect. In meta positions, charge cannot be delocalized, leading to less favorable stability.

Table of Substituent Effects

• Ortho and Para Directors: Moderate to strong activators such as –NH2, –NR2, –O, while some weak activators like Alkyl, Phenyl.

• Meta Directors: Strong deactivators such as –NO2, –CF3; weak deactivators include halogens.

Electrophilic Attack on Disubstituted Benzenes

• The strongest activator among substituents dominates the regioselectivity of electrophilic attack.

Guidelines for Regioselectivity

• Higher-ranking groups take precedence over lower-ranking ones within similar categories.

• Bulky substituents impede ortho attacks due to sterics; only preferentially yield meta products.

Synthetic Strategies for Substitution

• Strategies include interconversions, utilizing electrophilic substitutions tactically, and employing reversible blocking strategies with -SO3H.

Change in Directing Power of Substituents

• Nitration is often the simplest method to introduce a nitrogen substituent, convertible to amino via reduction, while oxidation can revert the nitrogen back to a nitro group.

Case Studies in Electrophilic Aromatic Substitution

• Direct bromination gives ortho and para products; using nitrobenzene can shift orientation. Similarly with alkanoyl leading to meta directors which can be reduced back to alkyl.

Reversible Sulfonation

• Efficient in achieving ortho-substituted benzenes by sulfonating first, followed by nitration, then desulfonation for position purity.

Protection Strategies

• Reduction of amine and hydroxy group activity can be achieved with protection groups, which moderately control reactivity toward electrophiles through advantage of deprotonation.

Reactivity of Polycyclic Benzenoid Hydrocarbons

• Naphthalene is particularly activated, readily undergoing electrophilic substitutions, preferentially at C1 owing to stability in carbocation resonance.

Regioselectivity in Substituted Naphthalenes

• Activating groups direct electrophilic substitution to the same ring while deactivating groups favor positions in the other ring (C5 and C8).

Polycyclic Aromatic Hydrocarbons and Cancer

• Compounds like benzo[a]pyrene are noted carcinogens linked with combustion processes, with biological conversion pathways forming active epoxides.

Important Concepts

• Benzene Substituent Classes: Activating vs. Deactivating structures, their electron donation or withdrawal characteristics, and how this impacts regioselectivity.

• Synthesis Strategies: Directing power manipulation, protecting groups, and reaction conditions' alterations for desired outcomes.

• Naphthalene Characterization: Electrophilic substitutions at C1 due to resonance stability.