Chapter 7 - Summary of Key Concepts

Substitution Reactions of Alcohols and Related Compounds

I. Substitution Reactions of Alcohols

  • Alcohols can act as weak acids and bases.
  • React with strong bases to form metal alkoxides (e.g., NaH).
  • React with active metals (Li, Na, K) to yield metal alkoxides as strong bases and nucleophiles.

Reactions to Form Alkyl Halides

  • Hydroxide ion (OH-) is a strong base and poor leaving group.
  • Requires conversion to a weaker base for SN1/SN2.
  • Hydrohalic acids (HCl, HBr, HI) promote reactions:
    • 2°, 3°, allylic, benzylic alcohols: follow SN1.
    • Methyl/primary alcohols: follow SN2.
Mechanism Details
  • Carbocations may rearrange (1,2 hydride shift, 1,2 alkyl shift).

Alkyl Sulfonates as Leaving Groups

  • Alcohols convert to alkyl sulfonates (sulfonyl esters) through:
    • Reaction with TsCl, MsCl, or TfCl.
  • Reaction mechanism involves:
    • Step 1: Formation of sulfonate ester (retains configuration).
    • Step 2: Reaction with nucleophiles (inversion in SN2).
Relative Leaving Group Ability
  • Order: CF3SO3 > I- > CH3SO3 > CH3C6H4SO3 > Br- > Cl-.

Halogenating Agents: (PBr3, SOCl2)

  • React with 1° and unhindered 2° alcohols to form alkyl halides.
  • Reaction with asymmetric 2° alcohols leads to inversion (SN2).
Reaction Mechanisms
  • PBr3 and SOCl2 both react similarly, resulting in halides.

The Mitsunobu Reaction

  • Converts alcohols to alkyl halides/esters.
  • Involves triphenyl phosphine and diethyl azodicarboxylate, adding HX (pKa < 12).
  • Inversion in configuration occurs if starting alcohol is chiral.

Synthesis and Reactions of Ethers

  • Preparation: Williamson synthesis using alkyl halides (or tosylate).
  • Reactions:
    • Ethers are resistant to oxidizing agents and strong bases — good solvents.
    • Cleaved by HBr/HI, mechanism resembles SN2.

Reactions of Epoxides

  • More reactive due to ring strain.
  • Ring opening depends on conditions:
    • Basic: nucleophile attacks least hindered carbon (SN2).
    • Acidic: nucleophile attacks more substituted carbon (SN1).

Substitution Reactions of Thiols and Thioethers

  • Thiols (-SH) are weaker leaving groups and undergo SN1 reactions as nucleophiles.
  • Thiolate anions formed via hydroxide or tertiary amine are good nucleophiles.
  • Thioethers (sulfides) can act as nucleophiles; trimethyl sulfonium iodide is a methylating agent.