We have seen many times when discussing the S_N2 mechanism that ethers are common products of nucleophilic substitution reactions.

They are synthesized by reacting alkyl halides or other substrates with good leaving groups with alkoxides:

 

 

This method of preparing ethers is called the Williamson Ether Synthesis, named after Alexander Williamson, who developed the reaction in 1850.

Notice that the alkyl halide reacts with the conjugate base (deprotonated form) of the alcohol, known as alkoxides. This is because alcohols are weak nucleophiles while alkoxides are good nucleophiles, favoring the S_N2 mechanism to obtain the product in high yields:

 

 

The alkoxides are prepared from the corresponding alcohols by deprotonating them with sodium hydride:

 

 

Besides the alkyl halides, tosylates and mesylates are other excellent candidates for reacting with alkoxides in Williamson synthesis:

 

  

Williamson Synthesis for Symmetrical and Unsymmetrical Ethers

Williamson synthesis can be used to prepare symmetrical and unsymmetrical ethers:

 

 

One difference with unsymmetrical ethers is that there are two ways you can synthesize them.

For example, isopropyl ethyl ether can be synthesized from the ethoxide ion (CH₃CH₂O^–) as the nucleophile and 2-chloropropane (Path a), or by reacting chloromethane with (CH₃)₂CHO^– acting as the nucleophile (Path b):

 

 

Usually, one of the paths is preferred, and to determine it, you need to keep in mind that the reaction goes by an S_N2 mechanism and S_N2 reactions are favored by less sterically hindered halides. Therefore, path is preferred since it is better to have CH₃Br rather than 2-chloropropane, which, as a secondary alkyl halide, is less reactive in S_N2 reactions.

Remember, using a bulky strong base such as sodium isopropoxide (CH₃)₂CHO^– or especially if it was tert-butoxide (tBuOK) favors the E2 elimination:

 

 

Check out this article on comparing the S_N2 and E2 reactions for a more detailed discussion.

The competition between E1, S_N1, E2 and S_N2 reactions is covered in the following posts:

S_N1, S_N2, E1, E2 – How to Choose the Mechanism

Is it S_N1, S_N2, E1, or E2 Mechanism with the Largest Collection of Practice Problems

 

Ethers through Intramolecular Substitution

Intramolecular Williamson ether synthesis is also possible if both the leaving group and the nucleophilic center are on the same molecule. For example, we can deprotonate 4-bromobutanol (4-bromobutan-1-ol) with a non-nucleophilic base such as sodium hydride, and let the resulting alkoxide do an intramolecular S_N2, forming the cyclic ether tetrahydrofuran:

Ask C

 

 

Notice that in a similar intramolecular Williamson reaction, the OH and Br are in anti-orientation, as that is the only possibility for the lone pairs in the HOMO orbital to access the LUMO antibonding orbital of the C–Br bond. Additionally, the OH and Br must be in axial positions to allow this antiperiplanar orientation. 

Check the article “S_N2 and E2 Reactions of Cyclohexanes” for more details and examples on the specifics of substitution and elimination reactions of chair cyclohexanes.

I’ve also written a separate article on the S_N1 and S_N2 reactions of alcohols – how alcohols act as weak nucleophiles, how the OH group can be converted into a better leaving group, and how these reactions proceed under different conditions.

 

Check out this 65-question, Multiple-Choice Quiz with a 3-hour Video Solution covering Nucleophilic Substitution and Elimination Reactions:

 

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