Williamson's synthesis

About Williamson's synthesis

This is the most important method for formation of ethers. It is a nucleophilic substitution reaction, Nucleophilic (S_N ² ) attack by alkoxide ion on an alkyl halide/alkyl sulphate / alkyl sulphonato which are known as substrates.Substrates should have good leaving group like X–, —OSO₂, —OSO₂R and it must have a primary alkyl group for good yield if substrates is tertiary than elimination occurs, giving alkenes. With a secondary alkyl halide, both elimination and substitution products are obtained.

R⎯X + Na⁺ ^-O⎯R' → R⎯O⎯R' + Na⁺ X^-

Reaction involves nucleophilic substitution of alkoxide ion for halide ion; it is strictly analogous to the formation of alcohols by treatment of alkyl halides with aqueous hydroxide.

Reaction Mechanism of Williamson's synthesis

Williamson's synthesis mechanism

Since alkoxides and alkyl halides are both prepared from alcohols, the Williamson method ultimately involves the synthesis of ether from two alcohols.

If we wish to make unsymmetrical dialkyl ether, we have a choice of two combinations of reagents; one of these is nearly always better than the other. In the preparation of tert-butyl ethyl ether, for example, the following combinations are conceivable:

Williamson's synthesis

Alkoxides are not only nucleophiles, but also strong bases which tend to react with alkyl halides by elimination, to yield alkenes. Whenever we are trying to carry out nucleophilic substitution, one must be aware of the competing elimination reaction. The tendency of alkyl halides to undergo elimination is 3^o > 2^o > 1^o.
In the above example, the use of the tertiary halide is rejected as it would be expected to yield mostly or all elimination product; hence the other combination is used.
Aromatic ethers are formed when phenoxides react with alkyl sulphates following S_N2 mechanism.

C₆H₅O–Na⁺+ CH₃—OSO₂O—CH₃→ C₆H₅OCH₃ + NaSO₂OCH₃
Sodium Phenoxide Dimethyl sulphate ether Methyl phenyl