Preparation

The simplest way of preparing ethers is the reaction between an alkoxide and an alkyl halide or sulfonate, following a typical S_N2 sequence:

This reaction was discovered by Williamson in the mid-19th century (1850).

Williamson synthesis: the alcohol is deprotonated by a base and the alkoxide attacks the halide R′X to give the ether R–O–R′

Typical bases: sodium, potassium, sodium hydride and sodium amide


Typical solvents	The same ROH in excess
		Dimethylsulfoxide (DMSO)	N,N-dimethyl formamide (DMF)	Hexamethyl phosphoramide (HMPA)

However, the usefulness of this reaction is heavily limited by the strong basicity of the alkoxide:

Outcome of the Williamson synthesis depending on the halide or sulfonate: SN2 with methyl and unhindered primary ones, E2 with branched primary, secondary and tertiary ones

Elimination is therefore a strong competitor to this reaction.

If the Williamson reaction is carried out intramolecularly, one obtains cyclic ethers
(Intramolecular S_N2 reaction).

Intramolecular Williamson synthesis: the alkoxide attacks the carbon bearing the leaving group in the same molecule and a cyclic ether is formed

Depending on the ring size that is being formed (m = n+2), the reaction proceeds at different rates:

Relative rate of formation of cyclic ethers depending on ring size: k3 ≥ k5 > k6 > k4 ≥ k7 > k8

For the ring formation to take place, both ends of the molecule must meet and collide. The higher 'n', the larger the number of bonds between the alkoxide and the leaving group. Those bonds have to be pretty ordered for the molecule ends to collide. This adds an unfavorable entropic term to the reaction rate. In the case of the epoxide this entropic contribution is the lowest. That's why the three-membered ring is the fastest to be formed, despite the ring tension in the final product.

Stereochemistry and conformation are essential for a reaction to proceed or not.

trans-2-Bromocyclohexanol forms the epoxide from the scarcely populated diaxial conformation, in which the alkoxide and the bromine are anti; in the diequatorial (gauche) one it does not react

The trans isomer of 2-bromocyclohexanol can lead to the epoxide, even though the right conformer is not the most populated - stable - one.

In cis-2-bromocyclohexanol no conformation allows the alkoxide to attack from behind the bromine: the epoxide is not formed

In turn, the cis isomer of 2-bromocyclohexanol does not have any conformer with the right arrangement for the alkoxide to attack, by the opposite side, the carbon bearing the leaving group.

The so-called crown ethers, the subject of a Nobel Prize, can be synthesized taking advantage of what has been called 'template effect'.

Template effect in the synthesis of 18-crown-6 ether: the potassium ion organizes the molecule and favours the intramolecular ring closure