Nef Reaction

What Is Nef Reaction?

The conjugate base of primary or secondary aliphatic nitro compounds is sulfuric acid hydrolyzed into aldehydes or ketones respectively. Tertiary nitro compounds can't be reacted because they can't be deprotonated. This conversion reaction was discovered by John Ulric Nef in 1894, and other conditions including oxidation and reduction were later developed to convert nitro compounds into carbonyl compounds. For example, activated dry silica gel, DBU, TiCl₃, 30% H₂O₂-K₂CO₃, or KMnO₄, cerium ammonium nitrate, Oxone or ozone. The above reagents acting on the conjugate base of nitro compounds can reduce side reactions and increase yields.

If the primary nitro compound is directly treated with sulfuric acid without deprotonation, carboxylic acid will be generated, and hydroxyimidic acid is its intermediate. This method can be used to synthesize the above two types of compounds.

• Reagents: Strong Base [Sodium hydroxide (NaOH) or potassium hydroxide (KOH)], Strong Acid [Dilute sulfuric acid (H₂SO₄) or hydrochloric acid (HCl)].
• Reactants: Primary or secondary nitroalkanes.
• Products: Aldehydes (from primary nitroalkanes), ketones (from secondary nitroalkanes).
• Reaction type: Formation of C=O bonds.
• Related reaction: Henry reaction.

Fig 1. Nef reaction and its mechanism. [1]

Mechanism of Nef Reaction

The mechanism under the most classic reaction conditions is: the nitrate compound is protonated and converted into a nitric acid compound, which is further protonated under the nucleophilic attack of the H2O molecule. The reaction process is determined by the pH of the reaction medium. Weak acid conditions are conducive to the formation of nitro compounds or some by-products (oxime or nitrite compounds), while strong acid conditions are conducive to the formation of carbonyl compounds.

Experimental Tips

• Under the action of DBU, the conjugate addition of nitro compounds with α,β-unsaturated compounds and Nef reaction can be carried out under the same reaction conditions. Therefore, this method can be used to synthesize γ-diketones, γ-diketoesters and conjugated cyclopentenones in one pot.
• The reaction products are greatly affected by the concentration of the acid. The lower the pH, the better the reaction results; when the pH>1, by-products such as oximes or nitrous compounds will be generated.
• The oxidation method can convert primary nitroalkanes into corresponding aldehydes or carboxylic acids, and secondary nitroalkanes into corresponding ketones; the reduction method can directly convert nitroalkanes into corresponding aldehydes, ketones or oximes; nitroalkenes can be converted into carbonyl compounds and oximes by various reducing agents.

Application Examples of Nef Reaction

• Example 1: A wonderful example of the application of Nef reaction in the total synthesis of natural products is the conversion of the intramolecular Diels-Alder reaction product into a carbonyl compound through the Nef reaction, thereby constructing the AB ring system of the natural product norzoanthamine. [2]
• Example 2: Wei-Lun Huang et al. achieved the enantioselective synthesis of aflatoxin systems with multiple stereocenters through a series of organocatalytic Michael-acetalization-reduction-Nef reactions with high enantioselectivity (90-99% ee). The first total synthesis of (-)- and (+)-microminutinin was also achieved through this scheme. [3]

Fig 2. Synthetic examples via Nef reaction.

Related Products

CAS No.	Structure	Product
82891-99-4		2-(2-Nitroethyl)-[1,3]dioxolane
17557-84-5		3-Azetidinone hydrochloride
21080-80-8		ethyl 4-cyclopropyl-2,4-dioxobutanoate
21573-10-4		1-Cyclopropylbutane-1,3-dione
21666-68-2		1-Cyclopropyl-3-(dimethylamino)-2-propen-1-one
501-94-0		2-(4-Hydroxyphenyl)Ethanol
19130-96-2		Duvoglustat Free Base
126-11-4		Tris(hydroxymethyl)nitromethane
90-64-2		DL-Mandelic acid sodium salt
13175-44-5		7-Octen-1-ol

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 386-388.
2. Williams, David R., et al. Organic Letters, 2000, 2(8), 1023-1026.
3. Huang, Wei-Lun, et al. Organic letters, 2017, 19(13), 3494-3497.