Overview
This lecture covers the structure, acidity, preparation, and reactions of alcohols and phenols, focusing on key methods, factors influencing acidity, and practical synthesis strategies.
Structure and Acidity of Alcohols and Phenols
- Alcohols contain a hydroxyl (OH) group attached to an sp³ hybridized carbon.
- Alcohols are more acidic than amines and alkanes, but less than hydrogen halides.
- Acidity is determined by the stability of the conjugate base; more stable bases mean stronger acids.
- Alcohols can be deprotonated by strong bases (e.g., sodium hydride) or metals (e.g., Na, K, Li).
- Resonance, induction (electron-withdrawing groups), and solvation (less steric hindrance) increase alcohol acidity.
- Alcohol pKa is typically 14–16.
Preparation of Alcohols
- Substitution Reactions:
- SN2 with primary alkyl halides and strong nucleophiles (e.g., NaOH).
- SN1 with tertiary substrates and weak nucleophiles (e.g., H₂O).
- Secondary substrates are less favorable for both SN1 and SN2.
- Addition Reactions to Alkenes:
- Acid-catalyzed hydration and oxymercuration-demercuration yield Markovnikov alcohols.
- Hydroboration-oxidation gives anti-Markovnikov alcohols.
- Reduction of Carbonyl Compounds:
- Aldehydes/ketones reduced to alcohols by H₂ (with metal), NaBH₄, or LiAlH₄.
- NaBH₄ is milder; LiAlH₄ is more reactive and requires non-protic solvents.
- Reduction of unsymmetrical ketones gives stereoisomers.
- Grignard Reactions:
- Grignard reagent (R-MgX) adds to aldehydes or ketones to form alcohols after protonation.
- Alcohols must be protected (e.g., with OTMS) prior to Grignard reactions to prevent side reactions.
Protection of Alcohols
- Protect alcohols with trimethylsilyl ether (OTMS) using TMS-Cl and Et₃N.
- Remove OTMS with TBAF after desired transformations.
Preparation of Phenols
- Industrially, phenols are prepared from benzene via cumene as an intermediate.
Reactions of Alcohols
- Substitution:
- Tertiary alcohols react via SN1 to form alkyl halides.
- Primary/secondary alcohols react via SN2 with SOCl₂/pyridine or PBr₃ to give chlorides/bromides.
- OTs (tosylate) formation improves leaving group ability.
- Elimination (E1, E2):
- Tertiary alcohols with strong acid yield alkenes (major product = most substituted).
- Oxidation:
- Chromic acid oxidizes secondary alcohols to ketones and primary alcohols to carboxylic acids.
- PCC or Swern oxidation (DMSO, (COCl)₂) oxidize primary alcohols to aldehydes, secondary to ketones.
Synthesis Strategies
- Multi-step syntheses involve converting between alcohols, alkenes, alkynes, and carbonyls using appropriate reagents and reaction types (addition, elimination, reduction, oxidation).
Key Terms & Definitions
- Alcohol — Organic compound with OH group on sp³ carbon.
- Phenol — Compound with OH group attached to an aromatic ring.
- Grignard Reagent — Organomagnesium halide (R-MgX), a nucleophile used to form C–C bonds.
- OTMS — Trimethylsilyl ether, used to protect alcohols.
- PCC — Pyridinium chlorochromate, oxidizes alcohols.
- Tosylate (OTs) — Good leaving group derived from alcohols using TsCl.
- E1/E2 Reaction — Elimination reactions forming double or triple bonds.
Action Items / Next Steps
- Practice synthesis and reaction mechanism problems from Chapter 12.
- Attempt unassigned practice problems and synthesis examples.
- Review key reagent functions and reaction conditions for alcohol transformations.