Mitsunobu reaction: benzyl alcohol + phthalimide → N-benzyl phthalimide
Ready to scaleSubstitutiondehydration
PPh3/DIAD-mediated dehydrative coupling of an alcohol with an acidic pronucleophile (pKa ≲ 13). Phthalimide as the nucleophile gives an N-alkyl phthalimide that hydrolyses to the free primary amine — the classic Gabriel-like sequence. SN2 mechanism with clean inversion of configuration at the alcohol carbon. PPh3 is oxidised to PPh3=O; DIAD is reduced to the corresponding hydrazine. Both byproducts complicate purification — chromatography is usually required.
Conditions
PPh3 (1.1 equiv) and DIAD (1.1 equiv) in dry THF (1.0 M based on alcohol). Add DIAD slowly to a stirred mixture at 0 °C, then warm to room temperature and stir for 4–12 h (overnight is safest). Argon atmosphere; DIAD reduces explosively at >100 °C.
Workup
Concentrate, redissolve in EtOAc, wash with sat. NaHCO3 + brine, dry MgSO4, evaporate. Column chromatography (hexane/EtOAc, gradient) removes PPh3=O and the spent hydrazine.
| Compound | Role | Equiv | MW (g/mol) | ρ (g/mL) | Safety |
|---|---|---|---|---|---|
| Benzyl alcohol100-51-6 · C7H8OBenzyl alcohol — primary alcohol; SN2 happens with inversion at this carbon. | reactant | 1.0 | 108.14 | 1.040 | Warning |
| Phthalimide85-41-6 · C8H5NO2Phthalimide — acidic NH (pKa ~8.3), comfortably below the Mitsunobu's ~13 pKa cutoff. Slight excess to compensate for incomplete deprotonation. | reactant | 1.1 | 147.13 | — | Not classified |
| Diisopropyl azodicarboxylate2446-83-5 · C8H14N2O4Diisopropyl azodicarboxylate (DIAD) — stoichiometric oxidant; reduced to the corresponding hydrazine. Add slowly at 0 °C; explosive on heating. | reagent | 1.1 | 202.21 | — | — |
| Triphenylphosphine603-35-0 · C18H15PTriphenylphosphine — stoichiometric reductant; oxidised to PPh3=O. | reagent | 1.1 | 262.29 | — | DangerSDS |
| Tetrahydrofuran109-99-9 · C4H8ODry THF — standard Mitsunobu solvent. Use freshly distilled or recently-opened anhydrous bottle; trace water deactivates the betaine intermediate. | solvent | — | 72.11 | 0.890 | DangerSDS |
| Benzylphthalimide2142-01-0 · C15H11NO2N-Benzyl phthalimide — white crystalline; mp 116 °C; recrystallises from EtOH. Hydrolyse with hydrazine in EtOH to liberate benzylamine (Gabriel synthesis). | product | — | 237.26 | — | Warning |