Ritter reaction

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Ritter reaction
Named after John J. Ritter
Reaction type Addition reaction
Identifiers
Organic Chemistry Portal ritter-reaction
RSC ontology ID RXNO:0000058

The Ritter reaction is a chemical reaction that transforms a nitrile into an N-alkyl amide using various electrophilic alkylating reagents. The original reaction formed the alkylating agent using an alkene in the presence of a strong acid:[1][2][3] The reaction has been the subject of several literature reviews.[3][4][5][6][7]

The Ritter reaction

Primary,[8] secondary,[7] tertiary,[9] and benzylic[10] alcohols,[3] as well as tert-butyl acetate,[11] also successfully react with nitriles in the presence of strong acids to form amides via the Ritter reaction.

History[edit]

The Ritter reaction is named after John J. Ritter, an American chemist who received his Ph.D. from Columbia University. In 1948, P. Paul Minieri, Ritter's student, submitted work on the reaction as his Ph.D. thesis.[12] The reaction still has significance today due to its applicability and reproducibility of amides via stabilized carbocations.[1]

Reaction mechanism[edit]

The Ritter reaction proceeds by the electrophilic addition of either the carbenium ion 2 or covalent species[13][14] to the nitrile. The resulting nitrilium ion 3 is hydrolyzed by water to the desired amide 5.

Animation of the reaction mechanism
The mechanism of the Ritter reaction

Applications[edit]

The Ritter reaction is most useful in the formation of amides in which the nitrogen has a tertiary alkyl group. It is also used in industrial processes as it can be effectively scaled up from laboratory experiments to large-scale applications while maintaining high yield. Real world applications include Merck’s industrial-scale synthesis of anti-HIV drug Crixivan (indinavir);[15] the production of the falcipain-2 inhibitor PK 11195; the synthesis of the alkaloid aristotelone;[16] and synthesis of Amantadine, an antiviral and antiparkinsonian drug.[17] Other applications of the Ritter reaction include synthesis of dopamine receptor ligands[16] and production of amphetamine from allylbenzene.[3][18]

A problem with the Ritter reaction is the necessity of an extremely strong acid catalyst in order to produce the carbocation. This corrosive type of chemical poses an environmental hazard for chemical waste and safety risk for running the reaction itself. However, other methods have been proposed in order promote carbocation formation, including photosensitized electron transfer[19] or direct photolysis.[20]

References[edit]

  1. ^ a b Ritter, John J.; Minieri, P. Paul (1948). "A New Reaction of Nitriles. I. Amides from Alkenes and Mononitriles". Journal of the American Chemical Society. 70 (12): 4045–8. doi:10.1021/ja01192a022. PMID 18105932. 
  2. ^ Ritter, John J.; Kalish, Joseph (1948). "A New Reaction of Nitriles. II. Synthesis of t-Carbinamines". Journal of the American Chemical Society. 70 (12): 4048–50. doi:10.1021/ja01192a023. PMID 18105933. 
  3. ^ a b c d Krimen, L.I.; Cota, Donald J. (1969). Adams, Rodger, ed. Organic Reaction Volume 17. London: John Wiley & Sons, Inc. pp. 213–326. doi:10.1002/0471264180.or017.03. ISBN 9780471196150. 
  4. ^ Zil'berman, E. N. (1960). "Some reactions of nitriles with the formation of a new nitrogen–carbon bond". Russian Chemical Reviews. 29 (6): 331–340. doi:10.1070/RC1960v029n06ABEH001235. 
  5. ^ Johnson, Francis; Madroñero, Ramón (1966). "Heterocyclic Syntheses Involving Nitrilium Salts and Nitriles under Acidic Conditions". Advances in Heterocyclic Chemistry. 6: 95–146. doi:10.1016/S0065-2725(08)60576-0. 
  6. ^ Rappoport, Zvi; Meyers, A. I.; Sircar, J. C. (1970). The Cyano Group (1st ed.). Charlottesville, VA: Wiley Interscience. pp. 341–421. doi:10.1002/9780470771242.ch8. ISBN 9780471709138. 
  7. ^ a b Bishop, Roger (1991). "Section 1.9 – Ritter-type Reactions". Comprehensive Organic Synthesis Volume 6: Heteroatom Manipulation. Comprehensive Organic Synthesis. pp. 261–300. doi:10.1016/B978-0-08-052349-1.00159-1. ISBN 9780080359298. 
  8. ^ Lebedev, Mikhail Y.; Erman, Mark B. (2002). "Lower primary alkanols and their esters in a Ritter-type reaction with nitriles. An efficient method for obtaining N-primary-alkyl amides". Tetrahedron Letters. 43 (8): 1397–1399. doi:10.1016/S0040-4039(02)00057-6. 
  9. ^ Ritter, J.J.; Kalish, J. (1964). "α,α-Dimethyl-β-phenethylamine". Organic Syntheses. 42: 16. doi:10.15227/orgsyn.042.0016. 
  10. ^ Parris, C.L. (1962). "N-Benzylacrylamide". Organic Syntheses. 42: 16. doi:10.15227/orgsyn.042.0016. 
  11. ^ Fernholz, H.; Schmidt, H. J. (1969). "Tert-Butyl Acetate as Alkylating Agent". Angewandte Chemie International Edition in English. 8 (7): 521. doi:10.1002/anie.196905211. 
  12. ^ Ritter, JJ; Minieri, PP (1948). "A New Reaction of Nitriles. I. Amides from Alkenes and Mononitriles". Journal of the American Chemical Society. 70 (12): 4045–8. doi:10.1021/ja01192a022. PMID 18105932. 
  13. ^ Booth, Brian L.; Jibodu, Kehinde O.; Proença, M. Fernanda J. R. P. (1983). "The chemistry of nitrilium salts. Part 2. The preparation of nitrilium trifluoromethanesulphonate salts and their reactions with some oxygen and sulphur nucleophiles". Journal of the Chemical Society, Perkin Transactions 1: 1067. doi:10.1039/P19830001067. 
  14. ^ García Martínez, A (1989). "An improved modification of ritter reaction". Tetrahedron Letters. 30 (51): 581. doi:10.1016/S0040-4039(00)95260-2. 
  15. ^ Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry; Oxford Press: New York, 2001.
  16. ^ a b Kurti, L.; Czako, B. (2005). Strategic Applications of Named in Organic Synthesis. Burlington, MA Elsevier Academic Press.
  17. ^ Vardanyan, R.; Hruby, V.J. Synthesis of Essential Drugs, 1st Ed. Amsterdam: Elsevier, 2006; pp. 137
  18. ^ Fujisawa and Deguchi, Chemical Abstracts, 52, 11965 (1958)
  19. ^ Mattes, Susan L.; Farid, Samir (1980). "Photosensitized electron-transfer reactions of phenylacetylene". Journal of the Chemical Society, Chemical Communications (3): 126. doi:10.1039/C39800000126. 
  20. ^ Kropp, Paul J.; Poindexter, Graham S.; Pienta, Norbert J.; Hamilton, David C. (1976). "Photochemistry of alkyl halides. 4. 1-Norbornyl, 1-norbornylmethyl, 1- and 2-adamantyl, and 1-octyl bromides and iodides". Journal of the American Chemical Society. 98 (25): 8135. doi:10.1021/ja00441a043.