Pd-catalyzed cross-coupling
Buchwald-Hartwig amination
How the Buchwald-Hartwig amination 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: ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu. Conditions: Toluene or dioxane, 80–110 °C. Bonds formed: Ar–N (C–N σ); bonds broken: Ar–Br; N–H. Stereochemistry: No new stereocentre; retention of aryl geometry. Rate and selectivity: Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination.
At a glance
Step 1: Oxidative addition (bulky ligand L)
Pd(0), supported by a bulky phosphine ligand, oxidatively adds an aryl halide, forming Ar–Pd(II)–X.
Step 2: Amine binds, base removes N–H
An amine coordinates to palladium and is deprotonated by base (an amido ligand forms directly on the metal) — this step plays the same structural role as transmetalation, putting a second group cis to the aryl.
Step 3: Reductive elimination
Reductive elimination forges the new C–N bond and regenerates Pd(0) — the same three-step logic as Suzuki coupling, but building carbon-nitrogen bonds instead of carbon-carbon ones.
Abbreviations and terms
- Ar
- Aryl group. Any aromatic ring substituent such as phenyl.
- X
- Halogen / leaving group. Cl, Br or I (sometimes any leaving group).
- L
- Ligand. A Lewis-base group (often a phosphine) bound to a metal centre.
- Ph
- Phenyl. –C₆H₅.
- Pd2(dba)3
- Tris(dibenzylideneacetone)dipalladium(0). Air-stable source of Pd(0).
- dba
- Dibenzylideneacetone. Weakly bound alkene ligand on Pd(0).
- BINAP
- 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl. Chiral bidentate phosphine for asymmetric catalysis.
How it compares with related reactions
| Buchwald-Hartwig amination | Heck reaction | Hiyama coupling | |
|---|---|---|---|
| Reagents | ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu | ArBr, alkene (e.g. methyl acrylate), Pd(OAc)₂/PPh₃, Et₃N | ArX, Ar′Si(OMe)₃ (or ArSiF₃), Pd(0) cat., TBAF (F⁻ activator) |
| Conditions | Toluene or dioxane, 80–110 °C | DMF or MeCN, 80–120 °C | THF or DMF, 60–100 °C |
| Stereochemistry | No new stereocentre; retention of aryl geometry | Syn insertion, syn β-H elimination; E-alkene favoured | Retention at sp² carbons; E/Z alkenes preserved |
| Rate / selectivity | Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination | Aryl adds to the less hindered alkene carbon | Transmetalation (needs F⁻ activation) is usually rate-limiting |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Buchwald-Hartwig amination?
ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu. Conditions: Toluene or dioxane, 80–110 °C.
Which bonds are formed and which are broken?
Formed: Ar–N (C–N σ). Broken: Ar–Br; N–H.
What is the stereochemical outcome?
No new stereocentre; retention of aryl geometry
What controls the rate or the selectivity?
Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam