The Passerini reaction is a chemical reaction involving an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form a α-acyloxy amide. This addition reaction is one of the oldest isocyanide-based multicomponent reactions and was first described in 1921 by Mario Passerini in Florence, Italy. It is typically carried out in aprotic solvents but can alternatively be performed in water, ionic liquids, or deep eutectic solvents. As isocyanides exhibit high functional group tolerance, chemoselectivity, regioselectivity, and stereoselectivity, the Passerini reaction has a wide range of synthetic applications.498px|center|The Passerini reaction
Mechanism
The Passerini reaction has been hypothesized to occur through two mechanistic pathways.
As the Mumm rearrangement requires a second carboxylic acid molecule, this mechanism classifies the Passerini reaction as an organocatalytic reaction.
Ionic mechanism
center|thumb|976x976px|Proposed ionic version of the Passerini reaction mechanism.
In polar solvents, such as methanol or water, the carbonyl is protonated before nucleophilic addition of the isocyanide, affording a nitrilium ion intermediate. This is followed by the addition of a carboxylate, acyl group transfer and proton transfer respectively to give the desired Passerini product. For example, polymer chain length and weight can adjusted through isocyanide stoichiometry, and polymer geometry can be influenced through starting reagents. To facilitate the Passerini reaction between bulky, sterically hindered reagents, a vortex fluidic device can be used to induce high shear conditions. These conditions emulate the effects of high temperature and pressure, allowing the Passerini reaction to proceed fairly quickly. The Passerini reaction can also exhibit enantioselectivity. Addition of tert-butyl isocyanide to a wide variety of aldehydes (aromatic, heteroaromatic, olefinic, acetylenic, aliphatic) is achieved using a catalytic system of tetrachloride and a chiral bisphosphoramide which provides good yield and good enantioselectivities. For other types of isocyanides, rate of addition of isocyanide to reaction mixture dictates good yields and high selectivities. The Passerini reaction has also been used to form sequence-defined polymers. Bifunctional substrates can be used to undergo post-polymerization modification or serve as precursors for polymerization. This reaction has also been used as a synthetic step in the total synthesis of commercially available pharmaceuticals such as telaprevir (VX-950), an antiviral sold by Vertex Pharmaceuticals and Johnson & Johnson.