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The Williamson ether synthesis is an SN2 reaction
The Williamson ether synthesis uses a base and an alkyl halide to convert an alcohol into a symmetrical or an unsymmetrical ether. The base deprotonates the alcohol to form an alkoxide that undergoes a nucleophilic substitution (SN2) reaction with the alkyl halide, producing the ether and a metal halide. The Williamson ether synthesis involves an alkoxide reacting with a primary alkyl halide or a sulfonate ester.
- Reagents: Base, Solvent (DMSO, DMF, etc.)
- Reactant: Aliphatic/Aromatic Alcohol and Alkyl, Allyl or Benzyl Halide
- Product: Ether
- Type of Reaction: SN2
- Bond Formation: R1-O-R2
- Dialkyl ethers are easily synthesized with a strong base such as NaH, KH, LHMDS, or LDA. Aryl ethers are synthesized with NaOH, KOH, K2CO3, or Cs2CO3.
- Use of dipolar aprotic solvents minimizes dehydrohalogenation side products.
- Tertiary or sterically hindered primary or secondary alkyl halides are prone to E2 elimination, affording an alkene product.
- Diaryl ethers cannot be prepared from phenoxides with unactivated aryl halides. The presence of copper metal or a Cu(I)-salt catalyst can make this reaction go (Ullmann biaryl ether synthesis), or if the aryl halide is activated with a strongly electron-withdrawing substituent.
- Alkali phenoxides may undergo C-alkylation in addition to O-alkylation.
- An Improved Williamson Ether Synthesis Using Phase Transfer Catalysis. Tetrahedron Letters. 1975, 16 (38), 3251–3254.
- Potassium Hydride in Paraffin: A Useful Base for Williamson Ether Synthesis. Tetrahedron Letters. 2010, 51 (27), 3545–3546.