Williamson Ether Synthesis

Core Concepts

In this organic chemistry tutorial, you will learn about Williamson Ether Synthesis, including its importance in organic chemistry, its chemical mechanism, and finally its notable limitations.

Topics Covered in Other Articles

• Functional Groups
• Ester Functional Group
• Amino Functional Group
• S_N2 vs S_N1 Reaction
• Diels-Alder Reaction

What is Williamson Ether Synthesis?

Williamson Ether Synthesis is a common organic chemistry reaction that makes ethers from oxides (or alcohols) and alkyl halides. English chemist Alexander Williamson first discovered and articulated the reaction in 1850, reacting chloroethane with potassium ethoxide, yielding diethyl ether. 

The reaction remains a staple of the organic chemistry laboratory, both in research and routine synthesis, due to its ease and versatility. With a few simple reagents under non-extreme conditions, you can easily synthesize a wide variety of ether compounds.

Williamson Ether Synthesis Mechanism

As mentioned before, Williamson ether synthesis involves an alcohol or oxide reacting with an alkyl halide. These reagents essentially perform an S_N2 mechanism. 

If an alcohol is used, a base is required to deprotonate the oxygen. Typically, chemists use a common strong base with an inert cation, such as sodium or potassium hydroxide. This base consequently deprotonates the alcohol, leaving behind a highly electronegative oxide species. Often, the base’s cation weakly associates with the oxide due to electrostatic attraction.

An alkoxide salt can serve as an alternative to alcohol, which instantly dissociates to generate the necessary oxide species.

Next, the S_N2 reaction begins. The oxide attacks the carbon bound to the halide, which then ejects the halide. This consequently generates an ether with alkyl groups that correspond to the original alcohol and alkyl halide species. 

You can also think of the free halide then interacting with the base cation, forming a salt. However, in solution, both ions likely stay as free spectators.

In the organic chemistry laboratory, this mechanism holds for most combinations of alcohols and alkyl halides. When both groups occur in the same molecule, cyclic ethers often spontaneously form. This occurs even if the groups only locate one carbon away, providing a reliable way of generating epoxides.

Though subject to steric limitations, as we explore in the next section, non-primary alkyl halides involve special mechanistic considerations. Since the reaction involves an S_N2 mechanism, the chirality of the carbon bound to the halide reverses. This is due to the backside attack of the oxide species

Williamson Ether Synthesis Limitations

In Williamson ether synthesis, there exist three important considerations that affect your ether production:

• Solvent
• Side product formation
• Catalysis

Solvent Limitations

To make sure your reactants work as intended, you need to carry out the reaction using a non-nucleophilic solvent. Common solvents for Williamson ether synthesis include toluene, acetonitrile, and N,N-dimethylformamide.

Nucleophilic solvents, like water or ethanol, can perform the S_N2 on the alkyl halide instead of the intended oxide species. Since solvents always exist “in excess” in a chemical reaction, virtually all your alkyl halide molecules will react with the solvent instead of your oxide,.

Side Product Limitations

The most important consideration for Williamson ether synthesis conditions concerns minimizing the formation of side products. In most cases, an alkene and alcohol serve as the most common side products, due to the reagents performing an E2 reaction instead of an S_N2.

The E2 mechanism tends to be favored when both or either of the oxide and alkyl halide is bulky. Excessive molecular bulk results in the reagents sterically inhibiting each other. In such cases, the oxide tends to react with the more-accessible Ɑ-hydrogen, instead of the sterically unavailable halide carbon.

As a result, primary oxides and primary halides tend to react fastest with the highest yields. Secondary oxides also tend to reliably generate the S_N2 product, but secondary halides often involve a significant loss in yield. Tertiary oxides and halides produce very little ether.

Catalysis Limitations

While many Williamson ether syntheses can take place without the help of a catalyst, less-favored reactants may require a little kinetic help. Silver oxide can serve as one such chemical helper, catalyzing the reaction by coordinate-bonding the halide. This makes the carbon more electrophilic, and thus more conducive to the S_N2 reaction,

Additionally, soluble iodine salts can also replace a less-reactive halide leaving group, such as chloride or bromide. However, this addition only proves helpful if you don’t have significant side product formation issues. This is because iodide makes both the S_N2 and E2 reactions easier.