What Is Wolff-Kishner Reduction Reaction?
Aldehydes and ketones are reduced to alkanes by hydrazones in the presence of bases. Kishner and Wolff reported this method in 1911 and 1912 respectively. The early reported steps were to add the pre-formed hydrazone to hot solid KOH or to heat it to 160~200℃ in a sealed tube with sodium ethoxide/ethanol. Wolff-Kishner reduction sometimes forms rearrangement products. Wolff-Kishner reduction is complementary to Clemmensen reduction, which reacts under acidic conditions. Therefore, Wolf-Kishner reduction is suitable for acid-sensitive substrates.
Improvements of Wolff-Kishner reduction: Among the many subsequent improvements, Huang-Minlon modification is the most commonly used. Other improvements under milder conditions include reactions in the presence of base t-BuOK, in DMSO, and at room temperature.
- Reagents: Hydrazine (NH2NH2, hydrate or anhydrous); strong base (e.g., NaOH, KOH, or sodium ethoxide); high-boiling solvent (e.g., ethylene glycol, diethylene glycol, or DMSO).
- Reactants: Aldehydes or ketones.
- Products: Alkanes (conversion of C=O to -CH2- group).
- Reaction type: Reduction (deoxygenation of carbonyl groups).
- Related reactions: Clemmensen reduction, Huang-Minlon modification, Curtius reaction, Corey-Bakshi-Shibata Reduction.
Fig 1. Wolff-Kishner reduction reaction and its mechanism. [1]
Mechanism of Wolff-Kishner Reduction
The Wolff-Kishner reduction proceeds via a deprotonation-hydrazone formation-decomposition pathway. A critical feature of this mechanism is the concerted elimination of N2, which drives the reaction thermodynamically and avoids reversibility.
- Hydrazone Formation: The carbonyl compound reacts with excess hydrazine to form a hydrazone intermediate. This step typically occurs under reflux in a polar solvent.
- Deprotonation and Rearrangement: Under strongly basic conditions, the hydrazone undergoes deprotonation to generate a resonance-stabilized diazenide intermediate. Heating at elevated temperatures (often 180-220 °C) facilitates the elimination of nitrogen gas, producing a carbanion.
- Protonation: The carbanion is quenched by a proton source (often water or the solvent), yielding the final alkane product.
Experimental Tips
- The original method of operation of this reaction is to reflux aldehyde or ketone, hydrazine and excess base in a high boiling point solvent. The water produced during the formation of hydrazone will reduce the temperature, resulting in a long reaction time (50-100 hours), and the need to use excess base and solvent.
- Huang-Minlon modification: After the hydrazone is generated, the water and excess hydrazine are removed in time by distillation. The reaction temperature can be increased to about 200°C and the reaction time can be shortened to 3-6 hours. This improvement not only improves the yield, but also allows the use of hydrazine hydrate and water-soluble base (KOH or NaOH).
- Esters, lactones, amides and lactams will hydrolyze under this reaction condition.
- Wolf-Kishner conditions are not suitable for the reduction of sterically hindered ketones (sterically hindered aldehydes or ketones require higher reaction temperatures) and are not suitable for the reduction of α,β-unsaturated ketones. In the latter case, the main product is pyrazole. Another modification of the Wolf-Kishner reduction is to form p-toluenesulfonylhydrazone, which is then reduced with reagents such as borane or metal hydrides (NaBH4, NaBH3CN). α,β-unsaturated ketones are reduced using this modification to form double bond migration products.
Application Examples of Wolff-Kishner Reduction
- Example 1: In the mid-stage enantioselective total synthesis of cyathane diterpenoids, Birch reductive methylation, modified Wolff–Kishner–Huang reduction, and carbene-mediated ring expansion were used as key reactions to provide a 5-6-7 tricyclic core with two anti-oriented all-carbon quaternary stereocenters at the junction of the C6 and C9 rings. [2]
- Example 2: Shun Wang et al. combined photoredox catalysis with the Wolff-Kishner reaction to achieve polarized difunctionalization of carbonyl compounds via a free radical-carbanion relay sequence. [3]
Fig 2. Synthetic examples via Wolff-Kishner reduction reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 583-585.
- Wu, Guo-Jie, et al. The Journal of Organic Chemistry, 2019, 84(6), 3223-3238.
- Wang, Shun, et al. Journal of the American Chemical Society, 2020, 142(16), 7524-7531.
