Chemistry

Conversion of 2,3-dihydroxy-thioxanthone to the corresponding ethyl halide ether

Step-by-step chemistry solution: Conversion of 2,3-dihydroxy-thioxanthone to the corresponding ethyl halide ether

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1. What the student is trying to do (plain‑language restatement)

The starting material is 2,3‑dihydroxy‑thioxanthone (a catechol fused to a thioxanthone skeleton).
The goal is to replace both phenolic OH groups with 2‑halo‑ethyl ethers so that the product looks like

   O‑CH2‑CH2‑X
   |
   (thioxanthone core)
   |
   O‑CH2‑CH2‑X

where X = Br (or Cl). In other words we need a bis‑(2‑haloethyl) ether of the catechol.

The student has already tried:

  • Direct SN2 alkylation with a protected ethyl‑tosylate – the first ether forms easily but the second is extremely sluggish and oxidation of the catechol occurs.
  • Mitsunobu coupling of each phenol with a halo‑alcohol – the first coupling works, the second stalls even after days, and the reaction mixture is littered with phosphine‑oxide and DIAD‑derived by‑products that are hard to remove.

The problem therefore is how to install the second 2‑haloethyl ether cleanly despite steric crowding and the oxidative sensitivity of the catechol.

Below is a complete, step‑by‑step synthetic solution that avoids the pitfalls encountered so far.

2. Worked solution (step‑by‑step)

Overview of the chosen strategy

  1. Mitsunobu coupling of each phenol with unprotected 2‑hydroxyethanol → bis‑(2‑hydroxyethyl) ether.
    Why? The primary alcohol is a far better nucleophile in the Mitsunobu reaction than a halide. Using the same reagent for both phenols guarantees identical reaction conditions for the two sites and eliminates the need for a protected (and sterically bulky) tosylate.

  2. Conversion of the two primary alcohols to bromides (or chlorides) by a clean Appel‑type halogenation (CBr₄/PPh₃) or by a two‑step mesylate‑then‑Finkelstein sequence.
    Why? Both methods work under neutral, non‑basic conditions, preserving the thioxanthone core and avoiding oxidation of the catechol.

  3. Optional work‑up / purification – simple aqueous work‑up removes phosphine‑oxides, and flash chromatography on silica (with a small amount of Et₃N to suppress phenolic adsorption) gives the pure bis‑(2‑haloethyl) ether.

Step 1 – Bis‑(2‑hydroxyethyl) ether via a double Mitsunobu reaction

Reagents (per phenolic OH) Typical scale (0.5 mmol SM)
2‑Hydroxyethanol (HO‑CH₂‑CH₂‑OH) 2.2 equiv (≈1.1 mmol)
Triphenylphosphine (PPh₃) 2.2 equiv (≈1.1 mmol)
DIAD (di‑isopropyl azodicarboxylate) 2.2 equiv (≈1.1 mmol)
Dry THF (or dry 1,4‑dioxane) 0.05 M (≈10 mL)
4 Å molecular sieves (activated) 1 g (per 0.5 mmol SM)
N₂ atmosphere, dark (to avoid photolysis) –

Procedure

  1. Set up a dry 50 mL Schlenk flask under N₂. Add activated 4 Å molecular sieves (to trap the water that is generated in the Mitsunobu step).
  2. Dissolve 2,3‑dihydroxy‑thioxanthone (0.5 mmol) in dry THF (≈10 mL). The solution will be faint yellow; stir until a homogeneous slurry forms.
  3. Add triphenylphosphine (1.1 mmol, 288 mg) in one portion. Stir for 5 min at 0 °C (ice bath).
  4. Add 2‑hydroxyethanol (1.1 mmol, 99 µL) dropwise via syringe while maintaining 0 °C. The mixture becomes slightly turbid.
  5. With a syringe pump (or dropwise by syringe), add a solution of DIAD (1.1 mmol, 224 µL) in dry THF (2 mL) slowly over 10 min while still at 0 °C.
  6. After the addition is complete, allow the mixture to warm to rt and stir overnight (≈16 h). TLC (hexane/ethyl acetate = 3:1, visualized with UV and KMnO₄) should show disappearance of the starting phenols and appearance of two very close spots corresponding to the mono‑alkylated intermediate and the bis‑alkylated product.
  7. Quench by adding sat. NH₄Cl (10 mL) at 0 °C, then extract with EtOAc (3 × 20 mL). Wash the combined organic layers with sat. NaHCO₃ (10 mL) and brine (10 mL). Dry over Na₂SO₄, filter, and concentrate.

Key points that make the second Mitsunobu work

  • Excess 2‑hydroxyethanol (2.2 equiv) drives the reaction to the bis‑product.
  • Molecular sieves remove the water that otherwise deactivates DIAD and promotes oxidation.
  • Low temperature during addition prevents decomposition of DIAD and minimizes side‑reactions.
  • Extended reaction time (overnight) gives the second phenol enough opportunity to react even though it is sterically hindered.

The crude mixture typically contains triphenylphosphine oxide (TPPO) and hydrazine dicarboxylate by‑products, both of which are removed in the next step.

Step 2 – Conversion of the terminal primary alcohols to bromides

Two reliable options are presented; the choice depends on what halide you need (Br > Cl) and on equipment availability.

Option A – Direct Appel bromination (CBr₄/PPh₃)

Reagents (per 0.5 mmol bis‑alcohol)  
Carbon tetrabromide (CBr₄) 2.5 equiv (≈1.25 mmol, 350 mg)
Triphenylphosphine (PPh₃) 2.5 equiv (≈1.25 mmol, 327 mg)
Dry CH₂Cl₂ (0.05 M) 10 mL
N₂ atmosphere, 0 °C → rt –

Procedure

  1. Dissolve the bis‑(2‑hydroxyethyl) ether (crude from Step 1, ≈0.5 mmol) in dry CH₂Cl₂ (10 mL) under N₂ and cool to 0 °C.
  2. Add PPh₃ (327 mg) in one portion, stir 5 min.
  3. Add CBr₄ (350 mg) in one portion, keep the temperature at 0 °C for 10 min, then allow the mixture to warm to rt and stir 2 h. TLC shows disappearance of the alcohol (the spot moves up, indicating a less polar bromide).
  4. Quench with sat. Na₂S₂O₃ (10 mL) to destroy any residual CBr₄, then extract with CH₂Cl₂ (3 × 20 mL). Wash organic layer with sat. NaHCO₃ (10 mL) and brine (10 mL). Dry (Na₂SO₄), filter, concentrate.
  5. Purify by flash chromatography (hexane/EtOAc = 4:1, 1 % Et₃N added to the eluent). The pure product is the bis‑(2‑bromoethyl) ether.

Advantages: One‑pot, neutral, no acidic or basic conditions; TPPO formed is removed on silica.

Option B – Two‑step mesylate → Finkelstein

  1. Mesylation
    • Reagents (0.5 mmol bis‑alcohol): MsCl (1.5 equiv, 75 µL), Et₃N (2 equiv, 140 µL), DMAP (0.1 equiv, 6 mg), dry CH₂Cl₂ (0.05 M).
    • Add MsCl dropwise at 0 °C, stir 1 h at rt. Work‑up (wash with sat. NaHCO₃, brine).
    • Isolate the bis‑mesylate (no chromatography needed; extract into EtOAc).
  2. Finkelstein substitution
    • Dissolve bis‑mesylate (≈0.5 mmol) in dry acetone (10 mL). Add NaI (3 equiv, 97 mg). Heat **reflux (≈56 °C)

Original question: Conversion of 2,3-dihydroxy-thioxanthone to the corresponding ethyl halide ether on Chemistry Stack Exchange, licensed CC BY-SA.

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