Alkyne synthesis — diazophosphonate
Seyferth-Gilbert / Ohira-Bestmann homologation
How the Seyferth-Gilbert / Ohira-Bestmann homologation 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: Seyferth–Gilbert: (MeO)₂P(O)CHN₂, KOtBu; Ohira–Bestmann: (MeO)₂P(O)C(N₂)C(O)CH₃, K₂CO₃, MeOH. Conditions: THF –78 °C (SG); MeOH, 25 °C (OB). Bonds formed: C≡C; N₂; (MeO)₂PO₂⁻; bonds broken: C=O; C–N₂. Stereochemistry: None (alkyne). Rate and selectivity: Carbene formation/1,2-H shift fast; addition is rate-limiting.
At a glance
Step 1: Diazomethylphosphonate anion adds to the aldehyde
Base deprotonates the Ohira-Bestmann or Seyferth-Gilbert reagent (a diazophosphonate), and this anion attacks an aldehyde's carbonyl carbon in an ordinary HWE-type addition, forming a betaine/oxaphosphetane intermediate.
Step 2: Collapse gives a vinyl diazo compound
Collapse of this intermediate ejects a phosphate byproduct exactly as in the HWE reaction, but here forms a vinyl diazo compound rather than a simple alkene, since the diazo group survives the olefination step untouched.
Step 3: –N₂, then 1,2-hydride shift
Loss of N₂ from this vinyl diazo species generates a vinylidene carbene, which rapidly undergoes a 1,2-hydride shift to give a terminal alkyne — a milder, more functional-group-tolerant one-carbon alkyne homologation than the Corey-Fuchs reaction covered earlier, avoiding its strongly basic double-elimination step.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- THF
- Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- KOtBu
- Potassium tert-butoxide. Strong, bulky alkoxide base – favours elimination over substitution.
- K2CO3
- Potassium carbonate. Mild inorganic base.
How it compares with related reactions
| Seyferth-Gilbert / Ohira-Bestmann homologation | Corey-Fuchs reaction | Aza-Wittig reaction | |
|---|---|---|---|
| Reagents | Seyferth–Gilbert: (MeO)₂P(O)CHN₂, KOtBu; Ohira–Bestmann: (MeO)₂P(O)C(N₂)C(O)CH₃, K₂CO₃, MeOH | 1) CBr₄, PPh₃ 2) 2 equiv n-BuLi, then H₂O | R–N=PPh₃ (from R–N₃ + PPh₃, Staudinger), aldehyde or ketone |
| Conditions | THF –78 °C (SG); MeOH, 25 °C (OB) | CH₂Cl₂, 0 °C; then THF, –78 °C | THF or toluene, 25–110 °C, anhydrous |
| Stereochemistry | None (alkyne) | No stereochemistry (alkyne is linear) | Imine E/Z set at ring collapse; no stereocentre needed |
| Rate / selectivity | Carbene formation/1,2-H shift fast; addition is rate-limiting | Wittig step fast; Li–Br exchange very fast at –78 °C | Cycloreversion is fast; driven by strong P=O bond (≈ 130 kcal/mol) |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Seyferth-Gilbert / Ohira-Bestmann homologation?
Seyferth–Gilbert: (MeO)₂P(O)CHN₂, KOtBu; Ohira–Bestmann: (MeO)₂P(O)C(N₂)C(O)CH₃, K₂CO₃, MeOH. Conditions: THF –78 °C (SG); MeOH, 25 °C (OB).
Which bonds are formed and which are broken?
Formed: C≡C; N₂; (MeO)₂PO₂⁻. Broken: C=O; C–N₂.
What is the stereochemical outcome?
None (alkyne)
What controls the rate or the selectivity?
Carbene formation/1,2-H shift fast; addition is rate-limiting
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