Organocatalysis — iminium activation
MacMillan iminium organocatalysis
How the MacMillan iminium organocatalysis 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: Chiral imidazolidinone·HCl (5–20 mol%), enal, nucleophile or diene. Conditions: MeOH/H₂O or CH₂Cl₂, 25 °C. Bonds formed: C–C or C–Nu at the β-carbon; bonds broken: C=C π (β-carbon). Stereochemistry: High ee: bulky group shields one iminium face. Rate and selectivity: Nucleophilic addition to the iminium is rate-limiting.
At a glance
Step 1: Condensation gives an iminium ion
A chiral imidazolidinone catalyst's secondary amine condenses with an α,β-unsaturated aldehyde, forming an iminium ion — this lowers the LUMO energy of the conjugated system, mimicking exactly what a Lewis acid does in ordinary conjugate addition activation, but through covalent, reversible catalysis instead of coordination.
Step 2: Nucleophile adds to the open face
The catalyst's bulky substituent blocks one face of the iminium, so an external nucleophile (in a Diels-Alder, Michael addition, or Friedel-Crafts reaction) approaches selectively from the open face — the identical facial-blocking strategy used by Evans' chiral auxiliary, just catalytic and removable instead of stoichiometric and covalently attached.
Step 3: Hydrolysis releases the product
Hydrolysis releases the enantioenriched product and regenerates the amine catalyst — this iminium-activation strategy is the electronic mirror image of proline's enamine activation, and together the two cover essentially the full scope of small-molecule carbonyl organocatalysis.
Abbreviations and terms
- Nu
- Nucleophile. An electron-rich species that donates an electron pair to form a new bond.
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- Lewis acid
- Lewis acid. Electron-pair acceptor (AlCl₃, BF₃, TiCl₄…) that activates carbonyls and halides.
- HCl
- Hydrochloric acid / hydrogen chloride. Strong acid; chloride is the nucleophile in additions/substitutions.
- LUMO
- Lowest unoccupied molecular orbital. The orbital that accepts electrons in a reaction.
- ee
- Enantiomeric excess. How much more of one enantiomer than the other is present.
How it compares with related reactions
| MacMillan iminium organocatalysis | Proline-catalyzed aldol reaction | CBS reduction (Corey-Bakshi-Shibata) | |
|---|---|---|---|
| Reagents | Chiral imidazolidinone·HCl (5–20 mol%), enal, nucleophile or diene | L-Proline (10–30 mol%), acetone (donor), aldehyde (acceptor) | (S)- or (R)-Me-CBS oxazaborolidine (5–10 mol%), BH₃·THF or BH₃·SMe₂ |
| Conditions | MeOH/H₂O or CH₂Cl₂, 25 °C | DMSO or DMF, 25 °C | THF, –20 to 25 °C, anhydrous |
| Stereochemistry | High ee: bulky group shields one iminium face | High ee; Zimmerman–Traxler-like TS with COOH H-bond | Predictable absolute configuration: hydride to the face set by the chiral boron-N framework |
| Rate / selectivity | Nucleophilic addition to the iminium is rate-limiting | C–C bond formation from enamine is rate-limiting | Hydride transfer is rate-limiting; catalyst turnover fast |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the MacMillan iminium organocatalysis?
Chiral imidazolidinone·HCl (5–20 mol%), enal, nucleophile or diene. Conditions: MeOH/H₂O or CH₂Cl₂, 25 °C.
Which bonds are formed and which are broken?
Formed: C–C or C–Nu at the β-carbon. Broken: C=C π (β-carbon).
What is the stereochemical outcome?
High ee: bulky group shields one iminium face
What controls the rate or the selectivity?
Nucleophilic addition to the iminium is rate-limiting
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam