Williamson ether synthesis

The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and a deprotonated alcohol (alkoxide). This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide ion with a primary alkyl halide via an S_N2 reaction. This reaction is important in the history of organic chemistry because it helped prove the structure of ethers.

The general reaction mechanism is as follows:

An example is the reaction of sodium ethoxide with chloroethane to form diethyl ether and sodium chloride:

The Williamson ether reaction follows an S_N2 (bimolecular nucleophilic substitution) mechanism. In an S_N2 reaction mechanism there is a backside attack of an electrophile by a nucleophile and it occurs in a concerted mechanism (happens all at once). In order for the S_N2 reaction to take place there must be a good leaving group which is strongly electronegative, commonly a halide.

In the Williamson ether reaction there is an alkoxide ion (RO⁻) which acts as the nucleophile, attacking the electrophilic carbon with the leaving group, which in most cases is an alkyl tosylate or an alkyl halide. The leaving site must be a primary carbon, because secondary and tertiary leaving sites generally prefer to proceed as an elimination reaction. Also, this reaction does not favor the formation of bulky ethers like di-tertbutyl ether, due to steric hindrance and predominant formation of alkenes instead.

The Williamson reaction is of broad scope, is widely used in both laboratory and industrial synthesis, and remains the simplest and most popular method of preparing ethers. Both symmetrical and asymmetrical ethers are easily prepared. The intramolecular reaction of halohydrins in particular, gives epoxides.

In the case of asymmetrical ethers there are two possibilities for the choice of reactants, and one is usually preferable either on the basis of availability or reactivity. The Williamson reaction is also frequently used to prepare an ether indirectly from two alcohols. One of the alcohols is first converted to a leaving group (usually tosylate), then the two are reacted together.

The alkoxide (or aryloxide) may be primary and secondary. Tertiary alkoxides tend to give elimination reaction because of steric hindrance. The alkylating agent, on the other hand is most preferably primary. Secondary alkylating agents also react, but tertiary ones are usually too prone to side reactions to be of practical use. The leaving group is most often a halide or a sulfonate ester synthesized for the purpose of the reaction. Since the conditions of the reaction are rather forcing, protecting groups are often used to pacify other parts of the reacting molecules (e.g. other alcohols, amines, etc.)