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SubstitutionIntermediate
Williamson Ether Synthesis
Also known as: Williamson Synthesis
Discovered by Alexander Williamson (1850)
General Equation
RO⁻ + R'X → R-O-R' (SN2)
Description
SN2 reaction between an alkoxide nucleophile and a primary (or methyl) alkyl halide to form an ether. The key planning decision is which oxygen becomes the alkoxide and which carbon bears the halide — always make the less hindered partner the halide.
Reaction Scheme
Reactants:
- • Alkoxide (RO⁻)
- • Primary alkyl halide (R'X)
Products:
- • Ether (R-O-R')
Reagents:
- • NaH or Na metal (to form alkoxide)
Conditions:
- • Anhydrous THF or DMF
Mechanism (2 steps)
1
Alkoxide formation: Treat the alcohol with NaH or Na metal to generate the alkoxide nucleophile (RO⁻).
Arrow: curvedRO⁻ Na⁺
2
SN2 displacement: The alkoxide attacks the primary alkyl halide from the back side, forming the ether product.
Arrow: curved
Must use 1° or methyl halide to avoid E2 elimination
Key Points to Remember
- ✓SN2 mechanism — requires primary or methyl alkyl halide
- ✓Bulky alkoxides + secondary/tertiary halides → E2 elimination instead
- ✓Planning: Make the more hindered alcohol the alkoxide, less hindered the halide
- ✓Good for both symmetrical and unsymmetrical ethers
- ✓Intramolecular version makes epoxides (3-membered ring ethers)
- ✓Tosylates (OTs) and mesylates (OMs) work as well as halides
Examples
Reactant:
Sodium ethoxide + Methyl iodide
Reagent:
THF
Product:
Methyl ethyl ether
Yield: 95%
Reactant:
Sodium phenoxide + Benzyl bromide
Reagent:
DMF
Product:
Benzyl phenyl ether
Yield: 90%
Synthetic Utility
The standard method for ether synthesis. Simple, reliable, and works for a wide range of substrates.
Limitations
- ⚠Secondary and tertiary halides undergo E2 instead
- ⚠Must plan which partner is alkoxide vs halide
- ⚠Requires anhydrous conditions
#SN2#ether#alkoxide#Williamson