Williamson Synthesis Nah Rx Roh

Alcohol Reactions: Williamson Synthesis using NaH, RX, and ROH

Williamson Ether Synthesis (NaH + R′–X) — Alkoxide Formation, SN2 Coupling, Intramolecular Rings

Sodium hydride (NaH) strips alcohols of their acidic proton, releasing H₂ and creating a highly nucleophilic alkoxide. Once formed, that alkoxide performs a backside SN2 attack on a compatible alkyl halide (R′–X) to build an ether. If the molecule already houses both the alcohol and a pendant halide, the same sequence becomes intramolecular and closes a ring. Secondary/tertiary electrophiles resist substitution—expect E2 elimination instead.

Comparisons: use PBr₃ or SOCl₂ when you need to convert the alcohol itself into a halide before substitution, or Appel conditions for mild halide installation.

Quick Summary

  • Reagents: alcohol (R–OH), strong base (NaH preferred), alkyl halide electrophile (R′–Cl/Br/I or sulfonate ester), polar aprotic solvent (THF/DMF/DMSO). Degas the H₂ before adding the halide.
  • Scope: methyl and primary halides react fastest; allylic/benzylic primaries are excellent. Secondary halides give mixtures or elimination; tertiary halides are purely E2.
  • Sequence: (1) NaH deprotonation → alkoxide + H₂; (2) add R′–X for SN2; (3) intramolecular halides cyclise spontaneously.
  • Intramolecular trigger: HO–(CH₂)ₙ–X forms 5–7 membered rings readily; emphasise the pendant “R” replacing X when describing products.
  • Competing E2: secondary or tertiary alkyl halides default to elimination; no ether forms (see Worked Example C).
  • Variants: phenoxides undergo Williamson ether formation with simple halides to give aryl ethers; sulfonate esters replace halides when a non-halide leaving group is needed.

Mechanism — Step 1: NaH Deprotonation

NaH removes the proton from an alcohol, releasing H2 and forming an alkoxide.
Hydride abstracts the alcohol proton, H₂ bubbles off, and the oxygen becomes an alkoxide (negative charge, no hydrogens).
  • Irreversibility: gaseous H₂ leaves the mixture, driving the equilibrium toward alkoxide formation.
  • Practical note: wait until gas evolution ceases; residual NaH indicates complete deprotonation.

Mechanism — Step 2: SN2 on R′–X

Alkoxide attack on an alkyl halide and departure of the leaving group.
The alkoxide lone pair performs a backside attack on R′–X, displacing the halide in a single concerted step and forging the ether bond.
  • Stereochemistry: inversion at the electrophilic carbon (classic SN2).
  • Leaving groups: iodides > bromides > chlorides; tosylates/mesylates work equivalently.
  • Solvent: polar aprotics keep the alkoxide solvated yet reactive.

Intramolecular Williamson (Ring Closure)

Alkoxide attacking a tethered alkyl halide to cyclise into an ether.
When the substrate already houses R′–X, the alkoxide attacks intramolecularly, expelling X and closing a ring (5–7 membered rings preferred).
  • Outcome: crown ethers, lactones, and mixed rings form rapidly; external electrophiles often cannot compete.
  • Design tip: tether length dictates ring size; ensure minimal strain for efficient cyclisation.

Competing E2 with Secondary/Tertiary R′–X

Secondary or tertiary alkyl halides cannot accommodate backside attack. The alkoxide switches to a base, abstracting a β-hydrogen and forming an alkene while X⁻ departs. Worked Example C highlights this failed ether attempt: the secondary halide is consumed via E2, so no ether is produced.

Worked Examples

1. n-Propanol + Methyl Bromide → Methyl n-propyl ether

Propanol reactant NaH / RX reagent button Ether product

Primary alkoxide + methyl halide → clean SN2 ether formation with inversion at the electrophilic carbon.

2. Phenoxide + Methyl Bromide → Anisole

Phenol reactant NaH / RX reagent button Anisole product

Phenoxide reacts with methyl bromide to give anisole—classic Williamson extension to aryl ethers.

3. Methoxide + sec-Butyl bromide (E2 dominates)

Methanol reactant NaH / RX reagent button + sec-Butyl bromide electrophile Elimination product (2-butene)

Deprotonated methanol attacks secondary sec-butyl bromide as a base, not a nucleophile, giving 2-butene via E2. No ether forms—secondary/tertiary electrophiles collapse to elimination.

Mechanistic Checklist

  1. Generate alkoxide completely (monitor for H₂ bubbles, add halide only after evolution stops).
  2. Choose a viable electrophile (methyl/primary/allylic/benzylic). Secondary/tertiary → elimination.
  3. Use polar aprotic solvent to keep the alkoxide reactive (THF, DMF, DMSO).
  4. Watch for intramolecular halides—they outcompete intermolecular ones.
  5. Keep water/ROH out once the alkoxide forms; proton donors quench the nucleophile.
  6. Consider leaving group swaps (tosylate/mesylate) if a halide isn’t available.
  7. State the R′ fragment explicitly in products/exams so students know which carbon chain moves.

Exam-Style Summary

  • Predictive prompt: “NaH, then 1-bromopropane with methanol.” → methoxide SN2 to give methyl propyl ether (inversion at the brominated carbon).
  • Intramolecular prompt: “HO–(CH₂)₅–Br + NaH.” → deprotonate and cyclise to THP (five-member ring).
  • Failure prompt: “NaH + tert-butyl bromide.” → elimination only; emphasise E2 rationale.
  • Mechanism request: always draw Step 1 (deprotonation) before Step 2 (SN2 or E2) to highlight sequencing.

Interactive Toolbox

  • Mechanism Solver – Draw the alcohol, pick “NaH / RX,” and preview the RDKit-rendered SN2 and intramolecular pathways directly from RDKit.
  • Reaction Solver – Search “NaH” or “Williamson” to quiz yourself on reagents, keywords, and short-form prompts.
  • IUPAC Namer – Double-check ether product names once you assign the R and R′ chains.

Ready to practice? Launch the Mechanism Solver or Reaction Solver and run the Williamson ether synthesis with your own substrates.