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.[1][2][3]

The Passerini reaction
Passerini reaction
Named after Mario Passerini
Reaction type Carbon-carbon bond forming reaction
Identifiers
Organic Chemistry Portal passerini-reaction
RSC ontology ID RXNO:0000244

This organic reaction was discovered by Mario Passerini in 1921 in Florence, Italy. It is the first isocyanide based multi-component reaction developed, and currently plays a central role in combinatorial chemistry.[4]

Recently, Denmark et al. have developed an enantioselective catalyst for asymmetric Passerini reactions.[5]

Reaction mechanism

Two reaction pathways have been hypothesized.

Ionic mechanism

In polar solvents such as methanol or water, the reaction proceeds by protonation of the carbonyl followed by nucleophilic addition of the isocyanide to give the nitrilium ion 3. Addition of a carboxylate gives intermediate 4. Acyl group transfer and amide tautomerization give the desired ester 5 .

The mechanism of the Passerini reaction

Concerted mechanism

In non-polar solvents and at high concentration a concerted mechanism is likely:[6]

Trimolecular Passerini reaction mechanism

This mechanism involves a trimolecular reaction between the isocyanide (R–NC), the carboxylic acid, and the carbonyl in a sequence of nucleophilic additions. The transition state TS# is depicted as a 5-membered ring with partial covalent or double bonding. The second step of the Passerini reaction is an acyl transfer to the neighboring hydroxyl group. There is support for this reaction mechanism: the reaction proceeds in relatively non-polar solvents (in line with transition state) and the reaction kinetics depend on all three reactants. This reaction is a good example of a convergent synthesis.

Scope

The Passerini reaction is used in many multicomponent reactions. For instance one preceded by a Horner-Wadsworth-Emmons reaction and forming a depsipeptide:[7]

Six component reaction Paravidino 2007

Passerini multicomponent reactions have found use in the preparation of polymers from renewable materials.[8]

gollark: I would recommend against #1, because weirdly enough people like being able to write, download and run programs.
gollark: In potatOS I do #2. Unfortunately the sandboxing implementation is about 500 lines of code, very version-specific because it runs half the BIOS for weird internal reasons, and has several known holes.
gollark: There are two ways around this:- make your "OS" unable to run arbitrary code and instead use a highly limited shell/GUI- sane sandboxing via providing no/a limited FS API to environments where you can run arbitrary code
gollark: The crux of the issue is that people can via a variety of methods write and run code which can edit your thing even if you pointlessly meddle with the shell.
gollark: No.

See also

References
  1. Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126–29.
  2. Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964–69.
  3. Banfi, L.; Riva, R. (2005). The Passerini Reaction. Org. React. 65. pp. 1–140. doi:10.1002/0471264180.or065.01. ISBN 978-0471264187..
  4. Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. Engl. 2000, 39, 3168–3210. (Review)
  5. Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667–76. doi:10.1021/jo050549m
  6. The Passirini Reaction L. Banfi, R.Riva in Organic Reactions vol. 65 L.E. Overman Ed. Wiley 2005 ISBN 0-471-68260-8
  7. A Flexible Six-Component Reaction To Access Constrained Depsipeptides Based on a Dihydropyridinone Core Monica Paravidino, Rachel Scheffelaar, Rob F. Schmitz, Frans J. J. de Kanter, Marinus B. Groen, Eelco Ruijter, and Romano V. A. Orru J. Org. Chem. 2007, 72, 10239–42 doi:10.1021/jo701978v
  8. Kreye, O.; Tóth, T.; Meier, M. J. Am. Chem. Soc., 2011, 133 (6), pp 1790–1792 doi:10.1021/ja1113003
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