Williamson ether synthesis
/ WILL-yum-son /
The Williamson ether synthesis is the standard, reliable way to build an ether — to join two carbon groups through an oxygen. Devised by Alexander Williamson in 1850, it remains the go-to method in modern labs because it is simple, general, and predictable. The recipe is to react an alkoxide ion with an alkyl halide.
Mechanically it is just an SN2 reaction with an oxygen nucleophile. First you make an alkoxide (R-O-) by deprotonating an alcohol with a strong base such as sodium hydride. That electron-rich oxygen then attacks the carbon of an alkyl halide (R'-X) from the back side, displacing the halide leaving group, and the new C-O-C bond of the ether snaps into place: R-O(-) + R'-X -> R-O-R' + X(-). Because it is an SN2, all the usual SN2 rules apply.
Those rules are the practical heart of the method. The alkyl halide must be one that does SN2 well — methyl or primary is ideal, secondary is sluggish, and tertiary fails entirely (a tertiary halide would just eliminate to an alkene under the basic alkoxide). So to make an unsymmetrical ether, always pair the more hindered group as the alkoxide with the least hindered group as the halide. For example, to make tert-butyl methyl ether you use tert-butoxide (the bulky alkoxide) plus iodomethane (the unhindered halide), never tert-butyl halide plus methoxide.
To make ethyl methyl ether: sodium ethoxide (CH3-CH2-O(-)) attacks iodomethane (CH3-I) in an SN2 step, giving CH3-CH2-O-CH3 and iodide. Pair the alkoxide with a methyl or primary halide for best results.
Alkoxide plus alkyl halide, by SN2 — the standard ether recipe.
Because it is SN2, never use a tertiary alkyl halide — it will eliminate to an alkene instead of forming the ether. Put the bulky group on the alkoxide and keep the halide methyl or primary.