18.2 Preparing Ethers

Williamson Ether Synthesis

Williamson ether synthesis is the most common lab method for making ethers. An alkoxide ion (the nucleophile) attacks an alkyl halide (the electrophile) in an SN2 reaction, forming a new C–O bond. Understanding when this works well and when it fails is critical for choosing the right synthetic route.

Mechanism

The core reaction: an alkoxide ion ($RO^-$) displaces a halide ($X^-$) from an alkyl halide ($R'X$) to produce an ether ($R{-}O{-}R'$).

Here's how it works step by step:

1. Generate the alkoxide. Treat an alcohol ($ROH$) with a strong base like sodium hydride ($NaH$) or sodium metal ($Na$). This deprotonates the alcohol to give $RO^-$.
2. SN2 attack. The alkoxide acts as a nucleophile and attacks the electrophilic carbon bearing the halogen ($Br$, $Cl$, or $I$). Because this is SN2, the attack happens from the backside of the leaving group.
3. Product forms with inversion. The halide departs, the ether forms, and the stereochemistry at the electrophilic carbon is inverted (Walden inversion).

Best conditions: a polar aprotic solvent (DMF, DMSO, or acetone) at room temperature or with gentle heating. Polar aprotic solvents don't solvate the nucleophile, keeping it reactive.

Limitations

Since this is an SN2 reaction, steric hindrance matters a lot:

• Tertiary alkyl halides almost never work. The bulky groups around the electrophilic carbon block backside attack, so elimination (E2) dominates instead of substitution.
• Secondary alkyl halides can work but often give a mix of substitution and elimination products. Use a less bulky alkoxide and keep temperatures low to favor SN2.
• Primary alkyl halides and methyl halides are ideal substrates.

When planning an unsymmetrical ether ($R{-}O{-}R'$ where R ≠ R'), you need to think carefully about which fragment becomes the alkoxide and which becomes the alkyl halide. The rule: make the less hindered partner the alkyl halide so the SN2 step proceeds cleanly. For example, to make methyl tert-butyl ether, use tert-butoxide as the nucleophile and methyl iodide as the electrophile, not the other way around.

Alkoxymercuration

Alkoxymercuration provides an alternative route to ethers starting from alkenes rather than alkyl halides. It's especially useful when you need Markovnikov regiochemistry and want to avoid the carbocation rearrangements that plague acid-catalyzed additions.

Mechanism (Two Steps)

Step 1: Alkoxymercuration

1. The alkene reacts with mercury(II) acetate ($Hg(OAc)_2$) in the presence of an alcohol ($ROH$).
2. The electrophilic mercury adds to the alkene, forming a three-membered mercurinium ion intermediate (similar to a bromonium ion). This bridged intermediate prevents carbocation rearrangements.
3. The alcohol attacks the mercurinium ion at the more substituted carbon (Markovnikov orientation), opening the ring and forming a mercury-containing ether.

Step 2: Demercuration (Reduction)

1. Treat the intermediate with sodium borohydride ($NaBH_4$) in aqueous base.
2. $NaBH_4$ replaces the mercury with hydrogen, giving the final ether product.

Regiochemistry and Stereochemistry

• Regiochemistry: Markovnikov. The $OR$ group ends up on the more substituted carbon of the original double bond.
• Stereochemistry: The mercurinium ion intermediate leads to anti addition of the alcohol and mercury across the double bond. However, after reduction with $NaBH_4$, the replacement of mercury by hydrogen is not stereospecific, so the final product is typically a mixture of stereoisomers.

The main drawback: mercury compounds are toxic and require careful handling and disposal.

Additional Ether Synthesis Methods

Acid-Catalyzed Dehydration of Alcohols

Two alcohol molecules lose water to form an ether under acidic conditions:

$2\,ROH \xrightarrow{H_2SO_4,\,\Delta} R{-}O{-}R + H_2O$

This works through protonation of one alcohol, followed by nucleophilic attack of the second alcohol on the protonated species. For primary alcohols, the mechanism is SN2-like. For secondary and tertiary alcohols, carbocation intermediates form, which opens the door to rearrangements and elimination side products.

• Best suited for symmetrical ethers from primary alcohols (e.g., diethyl ether from ethanol at 140°C with $H_2SO_4$)
• Unsymmetrical ethers give statistical mixtures of three products, making this method impractical for mixed ethers
• High temperatures can push the reaction toward alkene formation (elimination) instead of ether formation

Reaction of Alcohols with Diazomethane

$ROH + CH_2N_2 \rightarrow ROCH_3 + N_2$

Diazomethane ($CH_2N_2$) reacts with alcohols under mild conditions (room temperature, ether solvent) to produce methyl ethers selectively. It's a clean reaction that releases $N_2$ gas as the only byproduct.

The catch: diazomethane is both toxic and explosive, so it's only used in small-scale laboratory settings with proper safety precautions. It's also limited to making methyl ethers specifically.

Comparison of Ether Synthesis Methods

When choosing a method, ask yourself: What are my starting materials? Do I need a specific regiochemistry? Is the substrate too hindered for SN2? The answers will point you toward the right approach.