Nef reaction

The Nef reaction is an organic reaction describing the acid hydrolysis of a salt of a primary or secondary nitroalkane (1) to an aldehyde or a ketone (3) and nitrous oxide (4). The reaction has been the subject of several literature reviews.[1][2][3]

The Nef reaction

Nef reaction
Named after John Ulric Nef
Reaction type Substitution reaction
Identifiers
Organic Chemistry Portal nef-reaction
RSC ontology ID RXNO:0000157

The reaction was reported in 1894 by the chemist John Ulric Nef,[4] who treated the sodium salt of nitroethane with sulfuric acid resulting in an 85–89% yield of nitrous oxide and at least 70% yield of acetaldehyde. However, the reaction was pioneered a year earlier in 1893 by Konovalov,[5] who converted the potassium salt of 1-phenylnitroethane with sulfuric acid to acetophenone.

The Nef reaction should not be confused with the Nef synthesis.

Reaction mechanism

The reaction mechanism starting from the nitronate salt as the resonance structures 1a and 1b is depicted below:

The Nef reaction mechanism

The salt is protonated forming the nitronic acid 2 (in some cases these nitronates have been isolated) and once more to the iminium ion 3. This intermediate is attacked by water in a nucleophilic addition forming 4 which loses a proton and then water to the 1-nitroso-alkanol 5 which is believed to be responsible for the deep-blue color of the reaction mixture in many Nef reactions. This intermediate rearranges to hyponitrous acid 6 (forming nitrous oxide 6c through 6b) and the oxonium ion 7 which loses a proton to form the carbonyl compound.

Note that formation of the nitronate salt from the nitro compound requires an alpha hydrogen atom and therefore the reaction fails with tertiary nitro compounds.

Scope

The Nef reaction is frequently encountered in organic synthesis. It has been applied in carbohydrate chemistry as a chain-extension method for aldoses for example in the isotope labeling of C14-D-mannose and C14-D-glucose from D-arabinose and C14-nitromethane (the first step here is a Henry reaction):

The Nef reaction: chain extension

The opposite reaction is the Wohl degradation.

The reaction is also used in combination with the Michael reaction in the synthesis of γ-keto-carbonyls such as:[6]

Nef reaction in combination with Michael addition

or 2,5-heptanedione[7]

Hydrolysis of nitro compounds with strong acid without the intermediate salt stage results in the formation of carboxylic acids and hydroxylamine salts.

The hydrolysis step of the Nef reaction can also be performed with Lewis acids such as tin(IV) chloride[8] and iron(III) chloride[9] or oxidizing agents, such as oxone.[10]

References
  1. Noland, Wayland E. (1955). "The NEF Reaction". Chemical Reviews. 55 (1): 137–155. doi:10.1021/cr50001a003.
  2. Pinnick, Harold W. (1990). "The Nef Reaction". In Paquette, Leo A. (ed.). Organic Reactions Volume 38 (1st ed.). New York: Wiley. pp. 655–792. doi:10.1002/0471264180.or038.03. ISBN 9780471515944.
  3. Grierson, David S.; Husson, Henri-Philippe (1991). "4.7 – Polonovski- and Pummerer-type Reactions and the Nef Reaction". In Trost, Barry; Fleming, Ian (eds.). Comprehensive Organic Synthesis: Selectivity, Strategy and Efficiency in Modern Organic Synthesis, Volume 6 (1st ed.). New York: Pergamon. pp. 909–947. doi:10.1016/B978-0-08-052349-1.00175-X. ISBN 9780080359298.
  4. Nef, John Ulric (1894). "Ueber die Constitution der Salze der Nitroparaffine". Justus Liebigs Annalen der Chemie. 280 (2–3): 263–291. doi:10.1002/jlac.18942800209.
  5. Konovalov.,: J. Russ. Phys. Chem. Soc. 2 1893, 6(I), 509.
  6. A convenient synthesis of γ-functionalized cyclopentenones Nour Lahmar, Taïcir Ben Ayed, Moncef Bellassoued and Hassen Amri Beilstein Journal of Organic Chemistry 2005, 1:11 doi:10.1186/1860-5397-1-11
  7. McMurry, John E.; Melton, Jack (1977). "Conversion of Nitro to Carbonyl by Ozonolysis of Nitronates: 2,5-Heptandione". Organic Syntheses. 56: 36. doi:10.15227/orgsyn.056.0036.
  8. Miyashita, Masaaki; Yanami, Tetsuji; Yoshikoshi, Akira (1981). "Synthesis of 1,4-Diketones from Silyl Enol Ethers and Nitroolefins: 2-(2-Oxopropyl)cyclohexanone". Organic Syntheses. 60: 117. doi:10.15227/orgsyn.060.0117.
  9. Heinzelman, R. V. (1955). "o-Methoxyphenylacetone". Organic Syntheses. 35: 74. doi:10.15227/orgsyn.035.0074.
  10. Ceccherelli, Paolo; Curinia, Massimo; Marcotullioa, Maria Carla; Epifanoa, Francesco; Rosatia, Ornelio (1998). "Oxone® Promoted Nef Reaction. Simple Conversion of Nitro Group Into Carbonyl". Synthetic Communications. 28 (16): 3057–3064. doi:10.1080/00397919808004885.
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