Table of contents

1. A Review of General Chemistry5h 5m
2. Molecular Representations1h 14m
3. Acids and Bases2h 46m
4. Alkanes and Cycloalkanes4h 17m
5. Chirality3h 39m
6. Thermodynamics and Kinetics1h 22m
7. Substitution Reactions1h 48m
8. Elimination Reactions2h 30m
9. Alkenes and Alkynes2h 9m
10. Addition Reactions3h 19m
11. Radical Reactions1h 58m
12. Alcohols, Ethers, Epoxides and Thiols2h 42m
13. Alcohols and Carbonyl Compounds2h 17m
14. Synthetic Techniques1h 26m
15. Analytical Techniques:IR, NMR, Mass Spect7h 3m
16. Conjugated Systems6h 13m
17. Ultraviolet Spectroscopy51m
18. Aromaticity2h 34m
19. Reactions of Aromatics: EAS and Beyond5h 1m
20. Phenols55m
21. Aldehydes and Ketones: Nucleophilic Addition4h 56m
22. Carboxylic Acid Derivatives: NAS2h 51m
23. The Chemistry of Thioesters, Phophate Ester and Phosphate Anhydrides1h 10m
24. Enolate Chemistry: Reactions at the Alpha-Carbon1h 53m
25. Condensation Chemistry2h 9m
26. Amines1h 43m
27. Heterocycles2h 0m
28. Carbohydrates5h 53m
29. Amino Acids4h 20m
30. Peptides and Proteins2h 42m
31. Catalysis in Organic Reactions1h 30m
32. Lipids 2h 50m
33. The Organic Chemistry of Metabolic Pathways2h 52m
34. Nucleic Acids1h 32m
35. Transition Metals6h 14m
36. Synthetic Polymers1h 49m

19. Reactions of Aromatics: EAS and Beyond

Electrophilic Aromatic Substitution

Organic Chemistry

19. Reactions of Aromatics: EAS and Beyond

Electrophilic Aromatic Substitution

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Problem 13

Textbook Question

We have considered nucleophilic aromatic substitution of pyridine at the 2-position and 3-position but not at the 4-position. Complete the three possible cases by showing the mechanism for the reaction of methoxide ion with 4-chloropyridine. Show how the intermediate is stabilized by delocalization of the charge onto the nitrogen atom.

Verified step by step guidance

Identify the type of reaction: This is a nucleophilic aromatic substitution (NAS) reaction, where the methoxide ion (CH₃O⁻) acts as the nucleophile, and 4-chloropyridine is the substrate. The chlorine atom is the leaving group.

Determine the site of attack: The methoxide ion will attack the carbon atom at the 4-position of the pyridine ring, where the chlorine atom is attached. This attack occurs because the electron-deficient aromatic ring is activated by the electronegative nitrogen atom in pyridine.

Illustrate the addition step: The methoxide ion attacks the 4-position carbon, forming a negatively charged intermediate. This intermediate is a Meisenheimer complex, where the negative charge is delocalized across the ring and onto the nitrogen atom. Use resonance structures to show how the charge is stabilized. For example, one resonance structure will have the negative charge on the nitrogen atom, while others will show the charge on different carbons in the ring.

Depict the elimination step: After the intermediate is stabilized, the chlorine atom leaves as a chloride ion (Cl⁻), restoring aromaticity to the pyridine ring. This step completes the substitution reaction.

Summarize the overall reaction: The final product is 4-methoxypyridine, where the methoxide group has replaced the chlorine atom at the 4-position. The reaction mechanism demonstrates how the intermediate is stabilized by delocalization of the negative charge onto the nitrogen atom through resonance.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

Nucleophilic Aromatic Substitution (NAS)

Nucleophilic aromatic substitution is a reaction where a nucleophile replaces a leaving group on an aromatic ring. This process typically occurs when the aromatic compound has electron-withdrawing groups that stabilize the negative charge in the intermediate. In the case of pyridine, the nitrogen atom can influence the reactivity and stability of the intermediate formed during the substitution.

Mechanism of NAS

The mechanism of nucleophilic aromatic substitution generally involves two key steps: the formation of a Meisenheimer complex (an intermediate) and the elimination of the leaving group. In the case of 4-chloropyridine, the methoxide ion attacks the carbon bearing the chlorine, forming a negatively charged intermediate that can be stabilized by resonance, particularly through delocalization of the charge onto the nitrogen atom.

Resonance Stabilization

Resonance stabilization refers to the delocalization of electrons across adjacent atoms, which can lower the energy of a molecule and increase its stability. In the context of the intermediate formed during the nucleophilic substitution of 4-chloropyridine, the negative charge can be delocalized onto the nitrogen atom of the pyridine ring, allowing for multiple resonance structures that distribute the charge and enhance the stability of the intermediate.

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Show how each of the following compounds can be prepared from methyl phenyl ketone:

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Indicate how the following compounds can be synthesized from cyclohexanone and any other necessary reagents:

Textbook Question

Pyrrole undergoes electrophilic aromatic substitution more readily than benzene, and mild reagents and conditions are sufficient. These reactions normally occur at the 2-position rather than the 3-position, as shown in the following example.

b. Explain why pyrrole reacts more readily than benzene, and also why substitution occurs primarily at the 2-position rather than the 3-position.

Textbook Question

a. Draw resonance contributors to show why pyridine-N-oxide is more reactive than pyridine toward electrophilic aromatic substitution.

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What is the major product of the following reactions?

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What is the major product of the following reactions?

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Show how the following compounds can be prepared from the given starting material.

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When pyrrole is added to a dilute solution of D₂SO₄ in D₂O, 2-deuteriopyrrole is formed. Propose a mechanism to account for the formation of this compound.

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