Organometallic — Cr/Ni-catalyzed addition
Nozaki-Hiyama-Kishi (NHK) reaction
How the Nozaki-Hiyama-Kishi (NHK) reaction 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: Vinyl/aryl iodide or triflate, CrCl₂ (excess), cat. NiCl₂, aldehyde. Conditions: DMF or DMSO, 25 °C, inert atmosphere. Bonds formed: C–C; C–Cr (transient); O–Cr; bonds broken: C–I; C=O π. Stereochemistry: High anti diastereoselectivity via chair Zimmerman–Traxler TS. Rate and selectivity: Ni/Cr transmetalation is turnover-limiting; Cr(III) species do not enolise aldehydes.
At a glance
Step 1: Ni(0) insertion, then Ni → Cr transmetalation
A Ni(0) catalyst oxidatively adds a vinyl or aryl halide, then transfers the organic group to CrCl₂, generating an organochromium(III) species — chromium's high oxophilicity makes it an exceptionally mild, functional-group-tolerant nucleophile.
Step 2: Chelated chair transition state
This organochromium reagent adds directly to an aldehyde's carbonyl carbon through a rigid, chelated six-membered transition state (a Zimmerman-Traxler-type arrangement) — similar in spirit to the Grignard addition covered earlier, but far gentler and more selective.
Step 3: Workup releases the alcohol
Aqueous workup releases the allylic or homoallylic alcohol — the mild conditions let this reaction succeed on densely functionalized, complex substrates (like late-stage natural product intermediates) where a standard Grignard or organolithium would attack the wrong functional group.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- DMF
- N,N-Dimethylformamide. Polar aprotic solvent – dissolves ionic nucleophiles but does not H-bond to them, speeding SN2 and SNAr.
- DMSO
- Dimethyl sulfoxide. Polar aprotic solvent; also the oxidant in Swern/Kornblum-type reactions.
- TS
- Transition state. The highest-energy point on the pathway between two minima; it cannot be isolated.
How it compares with related reactions
| Nozaki-Hiyama-Kishi (NHK) reaction | Grignard addition to acetaldehyde | Grignard addition to an ester (2 equivalents → tertiary alcohol) | |
|---|---|---|---|
| Reagents | Vinyl/aryl iodide or triflate, CrCl₂ (excess), cat. NiCl₂, aldehyde | CH₃MgBr in Et₂O or THF; then H₃O⁺ | Ester (methyl benzoate), 2+ equiv. CH₃MgBr, then H₃O⁺ workup |
| Conditions | DMF or DMSO, 25 °C, inert atmosphere | Dry ether, 0 °C → 25 °C; strictly anhydrous | Dry Et₂O or THF, 0 °C → 25 °C; then aqueous NH₄Cl or dilute acid |
| Stereochemistry | High anti diastereoselectivity via chair Zimmerman–Traxler TS | Planar C=O: both faces attacked (racemic if new stereocentre) | Product has two identical groups: no stereocentre at carbinol C |
| Rate / selectivity | Ni/Cr transmetalation is turnover-limiting; Cr(III) species do not enolise aldehydes | Fast with aldehydes; RMgX is also a strong base — incompatible with acidic H | Ketone intermediate is more reactive than the ester, so no stop at the ketone |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Nozaki-Hiyama-Kishi (NHK) reaction?
Vinyl/aryl iodide or triflate, CrCl₂ (excess), cat. NiCl₂, aldehyde. Conditions: DMF or DMSO, 25 °C, inert atmosphere.
Which bonds are formed and which are broken?
Formed: C–C; C–Cr (transient); O–Cr. Broken: C–I; C=O π.
What is the stereochemical outcome?
High anti diastereoselectivity via chair Zimmerman–Traxler TS
What controls the rate or the selectivity?
Ni/Cr transmetalation is turnover-limiting; Cr(III) species do not enolise aldehydes
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam