Multicomponent reaction
Passerini reaction
How the Passerini 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: Carboxylic acid, aldehyde or ketone, isocyanide. Conditions: Aprotic solvent (CH₂Cl₂), high concentration, 25 °C. Bonds formed: C–C (isocyanide C); C–O (ester); N–H amide; bonds broken: C=O π; O–H; isocyanide divalent C. Stereochemistry: Racemic α-stereocentre (unless chiral components). Rate and selectivity: Third-order overall: faster at high concentration, slowed by polar protic solvents.
At a glance
Step 1: H-bond activation, isocyanide adds
A carboxylic acid protonates a ketone or aldehyde, activating it; an isocyanide's terminal carbon — unusually nucleophilic despite having no lone pair in the conventional sense — attacks the activated carbonyl carbon directly.
Step 2: Carboxylate traps the nitrilium ion
The resulting nitrilium ion is trapped intramolecularly by the carboxylate oxygen, which was generated in the very first step and has been waiting nearby the whole time.
Step 3: Mumm rearrangement
A final Mumm rearrangement — an intramolecular acyl transfer — converts this intermediate into a stable α-acyloxy amide, combining all three starting materials into one product in a single pot, with no isolated intermediates.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- TS
- Transition state. The highest-energy point on the pathway between two minima; it cannot be isolated.
How it compares with related reactions
| Passerini reaction | Ugi reaction | Bucherer-Bergs reaction | |
|---|---|---|---|
| Reagents | Carboxylic acid, aldehyde or ketone, isocyanide | Amine, aldehyde, carboxylic acid, isocyanide | Ketone, KCN, (NH₄)₂CO₃ |
| Conditions | Aprotic solvent (CH₂Cl₂), high concentration, 25 °C | MeOH or TFE, 0.5–2 M, 25 °C | EtOH/H₂O, 60–70 °C (sealed vessel) |
| Stereochemistry | Racemic α-stereocentre (unless chiral components) | Racemic α-centre unless chiral amine/aldehyde used | Quaternary C5; racemic unless prochiral control |
| Rate / selectivity | Third-order overall: faster at high concentration, slowed by polar protic solvents | Imine formation is pre-equilibrium; Mumm acyl transfer is irreversible and drives the reaction | Cyanide addition and carbamate cyclization are fast in the buffered medium |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Passerini reaction?
Carboxylic acid, aldehyde or ketone, isocyanide. Conditions: Aprotic solvent (CH₂Cl₂), high concentration, 25 °C.
Which bonds are formed and which are broken?
Formed: C–C (isocyanide C); C–O (ester); N–H amide. Broken: C=O π; O–H; isocyanide divalent C.
What is the stereochemical outcome?
Racemic α-stereocentre (unless chiral components)
What controls the rate or the selectivity?
Third-order overall: faster at high concentration, slowed by polar protic solvents
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