Nef reaction

Reaction mechanism

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

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 nitroxyl 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

Nef-type reactions are frequently encountered in organic synthesis, because they turn the Henry reaction into a convenient method for functionalization at the β and γ locations. Thus, for example, the reaction is combined with the Michael reaction in the synthesis of the γ-keto-carbonyl methyl 3-acetyl-5-oxohexanoate, itself a cyclopentenone intermediate:

In carbohydrate chemistry, they are a chain-extension method for aldoses, as in the isotope labeling of C14-Dmannose and C14-Dglucose from Darabinose and C14nitromethane (the first step here is a Henry reaction):

The opposite reaction is the Wohl degradation.

Variants

Nef's original protocol, using concentrated sulfuric acid, has been described as "violent". Strong-acid hydrolysis without the intermediate salt stage results in the formation of carboxylic acids and hydroxylamine salts, but Lewis acids such as tin(IV) chloride and iron(III) chloride give a clean hydrolysis. Alternatively, strong oxidizing agents, such as oxone, ozone, or permanganates, will cleave the nitronate tautomer at the double bond to form a carbonyl and nitrate. Oxophilic reductants, such as titanium salts, will reduce the nitronate to a hydrolysis-susceptible imine, but less selective reductants give the amine instead.

References

References

1. (1955). "The NEF Reaction". Chemical Reviews.
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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. (1977). "Conversion of Nitro to Carbonyl by Ozonolysis of Nitronates: 2,5-Heptandione". Organic Syntheses.
8. (2008). "Organic Synthesis: the disconnection approach". Wiley.
9. (1981). "Synthesis of 1,4-Diketones from Silyl Enol Ethers and Nitroolefins: 2-(2-Oxopropyl)cyclohexanone". Organic Syntheses.
10. (1955). "o-Methoxyphenylacetone". Organic Syntheses.
11. (1998). "Oxone Promoted Nef Reaction. Simple Conversion of Nitro Group into Carbonyl". Synthetic Communications.