Ether synthesis — SN2
Williamson ether synthesis
How the Williamson ether synthesis works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: R–OH + NaH (or Na, KOH); R′–X (1° or methyl). Conditions: THF or DMF, 25–80 °C. Bonds formed: C–O ether bond; bonds broken: O–H; C–X. Stereochemistry: Inversion at the alkyl halide carbon. Rate and selectivity: SN2; 2° / 3° halides give E2 alkene instead.
At a glance
Step 1: Base forms the alkoxide
Base deprotonates an alcohol to form an alkoxide — a much stronger, cleaner nucleophile than the neutral alcohol.
Step 2: Backside SN2 on a primary halide
The alkoxide performs a standard backside SN2 attack on a primary alkyl halide, exactly like the mechanism you learned first — no new chemistry, just a new nucleophile.
Step 3: Unsymmetrical ether
The product is an unsymmetrical ether. Because it's a clean SN2, this only works well with unhindered (primary, methyl) alkyl halides — a secondary or tertiary halide would give elimination instead.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- X
- Halogen / leaving group. Cl, Br or I (sometimes any leaving group).
- THF
- Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
- DMF
- N,N-Dimethylformamide. Polar aprotic solvent – dissolves ionic nucleophiles but does not H-bond to them, speeding SN2 and SNAr.
- NaH
- Sodium hydride. Insoluble, irreversible base: removes H⁺ and bubbles off H₂.
- KOH
- Potassium hydroxide. Strong aqueous/alcoholic base.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- SN2
- Bimolecular nucleophilic substitution. One concerted step with backside attack and inversion; rate = k[RX][Nu].
- E2
- Bimolecular elimination. Concerted base removal of β-H and loss of the leaving group (anti-periplanar).
How it compares with related reactions
| Williamson ether synthesis | Aza-Wittig reaction | Baeyer-Drewson indigo synthesis | |
|---|---|---|---|
| Reagents | R–OH + NaH (or Na, KOH); R′–X (1° or methyl) | R–N=PPh₃ (from R–N₃ + PPh₃, Staudinger), aldehyde or ketone | o-Nitrobenzaldehyde, acetone, aq. NaOH |
| Conditions | THF or DMF, 25–80 °C | THF or toluene, 25–110 °C, anhydrous | H₂O/acetone, 20–25 °C, then air |
| Stereochemistry | Inversion at the alkyl halide carbon | Imine E/Z set at ring collapse; no stereocentre needed | Product is the E-indigo, planar and strongly H-bonded |
| Rate / selectivity | SN2; 2° / 3° halides give E2 alkene instead | Cycloreversion is fast; driven by strong P=O bond (≈ 130 kcal/mol) | Aldol step fast; indigo precipitates as deep blue solid |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Williamson ether synthesis?
R–OH + NaH (or Na, KOH); R′–X (1° or methyl). Conditions: THF or DMF, 25–80 °C.
Which bonds are formed and which are broken?
Formed: C–O ether bond. Broken: O–H; C–X.
What is the stereochemical outcome?
Inversion at the alkyl halide carbon
What controls the rate or the selectivity?
SN2; 2° / 3° halides give E2 alkene instead
Study guides that help with this reaction
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go