Williamson Ether Synthesis - Conditions

Conditions

Since alkoxide ions are highly reactive, they are usually prepared immediately prior to the reaction, or are generated in situ. In laboratory chemistry, in situ generation is most often accomplished by the use of a carbonate base or potassium hydroxide, while in industrial syntheses phase transfer catalysis is very common. A wide range of solvents can be used, but protic solvents and apolar solvents tend to slow the reaction rate strongly, as a result of lowering the availability of the free nucleophile. For this reason, acetonitrile and N,N-dimethylformamide are particularly commonly used.

A typical Williamson reaction is conducted at 50–100 °C and is complete in 1–8 hours. Often the complete disappearance of the starting material is difficult to achieve, and side reactions are common. Yields of 50–95% are generally achieved in laboratory syntheses, while near-quantitative conversion can be achieved in industrial procedures.

Catalysis is not usually necessary in laboratory syntheses. However, if an unreactive alkylating agent is used (e.g. an alkyl chloride) then the rate of reaction can be greatly improved by the addition of a catalytic quantity of a soluble iodide salt (which undergoes halide exchange with the chloride to yield a much more reactive iodide, a variant of the Finkelstein reaction). In extreme cases, silver salts may be added for example silver oxide :

The silver ion coordinates with the halide leaving group to make its departure more facile. Finally, phase transfer catalysts are sometimes used (e.g. tetrabutylammonium bromide or 18-crown-6) in order to increase the solubility of the alkoxide by offering a softer counter-ion.