Passerini reaction

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. It is a third order reaction; first order in each of the reactants. The Passerini reaction is often used in combinatorial and medicinal chemistry with recent utility in green chemistry and polymer chemistry. As isocyanides exhibit high functional group tolerance, chemoselectivity, regioselectivity, and stereoselectivity, the Passerini reaction has a wide range of synthetic applications.

The Passerini reaction has been hypothesized to occur through two mechanistic pathways. The reaction pathways are dependent on the solvent used.

A concerted mechanism, seen in S_N2 and Diels−Alder reactions, is theorized to occur when the Passerini reagents are present at high concentration in aprotic solvents.

This mechanism involves a trimolecular reaction between the isocyanide, carboxylic acid, and carbonyl in a sequence of nucleophilic additions. The reaction proceeds first through an imidate intermediate and then undergoes Mumm rearrangement to afford the Passerini product.

As the Mumm rearrangement requires a second carboxylic acid molecule, this mechanism classifies the Passerini reaction as an organocatalytic reaction.

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.

Molecular weights of polymers synthesized through the Passerini can be controlled through stoichiometric means. 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.

Apart from forming α-acyloxy amide products, the Passerini reaction can be used to form heterocycles, polymers, amino acids, and medicinal products.