8 Aromatic Hydrocarbons II: Structures & Reactions

Medicinal and Pharmaceutical Chemistry: Aromatic Hydrocarbons II

  • Course Title: Medicinal and Pharmaceutical Chemistry (MEDCHEM.8)
  • Focus: Structures & Reactions of Aromatic Hydrocarbons

Recommended Reading

  • Textbook: Organic Chemistry with Biological Applications (3rd Ed) by John McMurry
  • Key Chapters:
  • Chapter 9:
    • 9.1: Naming of aromatic compounds
    • 9.2: Structure and stability of benzene
    • 9.3: Aromaticity and the Huckel 4n + 2 Rule
    • 9.5: Polycyclic aromatic compounds
    • 9.6: Reactions of aromatic compounds: Electrophilic substitution reactions
    • 9.7: Alkylation and acylation of aromatic rings: the Friedel-Crafts reaction
    • 9.8: Substituent effects in electrophilic substitution

Learning Objectives

  • Understand activating/deactivating effects of substituents
  • Recognize directing effects of substituents in electrophilic substitution
  • Comprehend resonance effects in aromatic compounds (phenol, aniline, chlorobenzene)
  • Apply substituent directing effects to perform synthesis
  • Recall other reactions involving benzene derivatives

Lecture Outline

  1. Carbocations and their resonance forms
  2. Naming di-substituted benzenes
  3. Concept of directing effects
  4. Impact of substituents on reaction rates
  5. Activators and Deactivators
  6. Directing effects of electron donating groups (EDG)
  7. Directing effects of electron withdrawing groups (EWG)
  8. Unique behavior of halogens
  9. Synthesis of tri-substituted benzenes
  10. Overview of other reactions involving benzene derivatives

Electrophilic Aromatic Substitution

  • Generell Mechanism:
  1. Generation of the electrophile (e.g., bromine add to benzene)
  2. Electrophilic attack and formation of a benzenium ion
  3. Deprotonation/reformation of the aromatic ring
  4. Regeneration of the catalyst

Carbocation Stability

  • Resonance Forms:
  • Positive charge can be delocalized across multiple positions, providing greater stability.
  • Stability of carbocations affects reactivity and the favored positions for substitution.

Naming Di-substituted Benzenes

  • Common Nomenclature:
  • Ortho (o-): 1,2-
  • Meta (m-): 1,3-
  • Para (p-): 1,4-
  • Example: Ortho-dibromobenzene (1,2-dibromobenzene)

Directing Effects in Substitution Reactions

  • Electron Donating Groups (EDGs) (e.g., -CH3):

  • Increase electron density on the ring, accelerating electrophilic substitution.

  • Direct substitution predominantly occur at ortho and para positions.

  • Electron Withdrawing Groups (EWGs) (e.g., -NO2):

  • Decrease electron density, slowing down the reaction.

  • Typically direct substitution at the meta position.

  • Special Case: Halogens:

  • EWG by induction, but EDG by resonance, favoring ortho/para substitution.

Conclusion

  • Understanding the activation or deactivation efficiency of substituents is crucial for predicting reaction outcomes in aromatic chemistry.
  • Proficiency in these concepts will facilitate the design and synthesis of complex aromatic compounds in medicinal chemistry.