Wolff-Kishner Reduction
Introduction to the Wolff-Kishner Reduction
The Wolff-Kishner reduction was independently discovered by the Russian chemist Nikolai Kishner in 1911 and the German chemist Ludwig Wolff in 1912.[1,2]
In the Wolff-Kishner reduction, an aldehyde or ketone undergoes a reduction to form an alkane. Specifically, this reaction converts a carbonyl group(C=O) into a methylene group(-CH2-).[3,4]
Fig 1. Wolff - Kishner Reduction Reaction
The Wolff-Kishner reduction takes place at elevated temperatures (100-200˚C) and in the presence of a base. This distinguishes it from the Clemmensen reduction, which is another commonly used reduction reaction that occurs under acidic conditions. The choice between these two reactions depends on the sensitivity of the substrates involved: the Wolff-Kishner reduction is suitable for acid-sensitive substrates, whereas the Clemmensen reduction is more favorable for base-sensitive substrates.
Mechanism of the Wolff–Kishner Reduction
The Wolff-Kishner reduction involves two main steps: the formation of intermediate hydrazone and the reduction of said hydrazone to alkanes.[5-12]
Formation of Hydrazone
Hydrazine (N2H4) forms hydrazone when reacting with aldehydes or ketones under weakly acidic conditions. In this reaction, hydrazine acts as a nitrogen-containing nucleophilic reagent.
Fig 2. The Transformation of a Ketone into a Hydrazone
The mechanism of hydrazone formation is as follows: first, hydrazine makes a nucleophilic attack on the carbonyl group. This is followed by a proton transfer step promoted by an acidic environment. Next, water departs to form a C=N double bond. The resulting intermediate is then deprotonated to obtain the intermediate hydrazone.
Fig 3. The Mechanism of the Formation of Hydrazone
The Reduction of Hydrazone
Under basic conditions, hydrazone is readily reduced to alkanes - he end product of the Wolff-Kishner reduction reaction.
Fig 4. The Reduction of a Hydrazone into an Alkane
The mechanism of hydrazone reduction is as follows: first, the alkaline environment deprotonates the NH2 of the hydrazone to form a resonance-stabilized intermediate. Then, the negatively charged carbon of this intermediate is protonated. the NH loses its proton and forms a carbon negative ion (a carbon with non-shared electron pairs). Finally, the carbon negative ion is protonated to become an alkane.
It is important to note that the discharge of nitrogen from the solution in the form of bubbles forces the completion of the reaction (according to Le Chatelier's principle), thus allowing the product to achieve an efficient yield.
Fig 5. The Mechanism of the Reduction of Hydrazone
Wolff-Kishner-Huang Minlon Reduction
Many of the optimizations devoted to the Wolff-Kishner reduction have focused on the more efficient formation of hydrazone intermediates by removing water and on the faster decomposition of hydrazone by increasing the reaction temperature.[7,8] Some newer optimizations offer more significant advances and allow the reaction to be carried out under rather mild conditions. Among them, the Wolff-Kishner-Huang Minlon reduction reaction was the first organic chemical reaction named after a "Chinese" person.
In 1946, Minglong Huang reported a modified Wolff-Kishner ketone reduction method in which excess hydrazine and water were removed by distillation after hydrazone formation.[11,12] Even when anhydrous hydrazine is used in hydrazone formation, the cooling effect of water generated in hydrazone formation usually leads to longer reaction times and harsh reaction conditions. The optimized method consists of refluxing the carbonyl compound in 85% hydrazine hydrate with three equivalents of sodium hydroxide, evaporating the water and excess hydrazine, and completing the reflux after 3 to 4 hours when the temperature reaches 200°C. The use of this method resulted in significantly shorter reaction times and higher yields.
Wolff-Kishner Reduction Application
Wolff-Kishner reduction has been applied to the synthesis of Scopadulcic Acid B[13], Aspidospermidine[14,15], and dysidiolide[16]. Wolff-Kishner reduction is an effective tool in organic chemistry synthesis. For example, Ishibashi and colleagues used Wolff-Kishner-Huang Minlon reduction as one of the final steps in the synthesis of (±)-Aspidospermidine. The hydrazone was formed at 160 °C followed by the removal of distillable material and then heated to 210°C overnight. the carbonyl group reduced during the Wolff-Kishner reduction was essential for the first few steps of the synthesis. The tertiary amide is stable under reaction conditions and is subsequently reduced by lithium aluminum hydride. [15]
Wolff-Kishner reduction has also been used for the synthesis of kilo-functionalized imidazole substrates. Several alternative reduction methods were investigated, but all tested conditions were unsuccessful.Wolff-Kishner reduction solves the safety problem for large-scale production and provides a highly optimized synthesis of the product in good yields. [17]
Reference
1. Kishner, N (1911). "Wolff–Kishner reduction; Huang–Minlon modification". J. Russ. Phys. Chem. Soc. 43: 582–595.
2. Wolff, L. (1912). "Chemischen Institut der Universität Jena: Methode zum Ersatz des Sauerstoffatoms der Ketone und Aldehyde durch Wasserstoff. [Erste Abhandlung]"Justus Liebig's Annalen der Chemie. 394: 86–108. https://doi.org/10.1002/jlac.19123940107
3. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 1835, ISBN 978-0-471-72091-1
4. Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. p. 453. ISBN 978-0387683546.
5. Szmant, H. H.; Harmuth, C. M. (1964). "The Wolff-Kishner Reaction of Hydrazones". Journal of the American Chemical Society. 86 (14): 2909. https://doi.org/10.1021/ja01068a028.
6. Szmant, H. H. (1968). "The Mechanism of the Wolff-Kishner Reduction, Elimination, and Isomerization Reactions". Angewandte Chemie International Edition in English. 7 (2): 120–128. https://doi.org/10.1002/anie.196801201.
7. Szmant, H. H.; Roman, M. N. (1966). "The Effect of Dimethyl Sulfoxide on the Rate of the Wolff-Kishner Reaction of Benzophenone Hydrazone1". Journal of the American Chemical Society. 88 (17): 4034. https://doi.org/10.1021/ja00969a025.
8. Szmant, H. H.; Alciaturi, C. E. (1977). "Mechanistic aspects of the Wolff-Kishner reaction. 6. Comparison of the hydrazones of benzophenone, fluorenone, dibenzotropone, and dibenzosuberone". The Journal of Organic Chemistry. 42 (6): 1081. https://doi.org/10.1021/jo00426a034.
9. Herr, C. H.; Whitmore, F. C.; Schiessler, R. W. (1945). "The Wolff-Kishner Reaction at Atmospheric Pressure". Journal of the American Chemical Society. 67 (12): 2061. https://doi.org/10.1021/ja01228a002.
10. Soffer, M. D.; Soffer, M. B.; Sherk, K. W. (1945). "A Low Pressure Method for Wolff—Kishner Reduction". Journal of the American Chemical Society. 67 (9): 1435. https://doi.org/10.1021/ja01225a004
11. Huang-Minlon, [N. A. (1946). "A Simple Modification of the Wolff-Kishner Reduction". Journal of the American Chemical Society. 68 (12): 2487–2488. https://doi.org/10.1021/ja01216a013
12. Huang-Minlon, [N. A. . (1949). "Reduction of Steroid Ketones and other Carbonyl Compounds by Modified Wolff--Kishner Method". Journal of the American Chemical Society. 71 (10): 3301–3303. https://doi.org/10.1021/ja01178a008
13. Overman, L. E.; Ricca, D. J.; Tran, V. D. (1993). "First total synthesis of scopadulcic acid B". Journal of the American Chemical Society. 115 (5): 2042. https://doi.org/10.1021/ja00058a064
14. Marino, J. P.; Rubio, M. B.; Cao, G.; De Dios, A. (2002). "Total Synthesis of (+)-Aspidospermidine: A New Strategy for the Enantiospecific Synthesis of Aspidosperma Alkaloids". Journal of the American Chemical Society. 124 (45): 13398–13399. https://doi.org/10.1021/ja026357f.
15. Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.; Matsuo, J. I.; Ishibashi, H. (2013). "Regioselective Inter- and Intramolecular Formal \4+2] Cycloaddition of Cyclobutanones with Indoles and Total Synthesis of (±)-Aspidospermidine". Angewandte Chemie International Edition. 52 (3): 906–10. https://doi.org/10.1002/anie.201206734
16. Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada, Y. (2001). "Total Synthesis of Natural Dysidiolide". The Journal of Organic Chemistry. 66 (4): 1429–1435. https://doi.org/10.1021/jo0015772
Kuethe, J. T.; Childers, K. G.; Peng, Z.; Journet, M.; Humphrey, G. R.; Vickery, T.; Bachert, D.; Lam, T. T. (2009). "A Practical, Kilogram-Scale Implementation of the Wolff−Kishner Reduction". Organic Process Research & Development. 13 (3): 576. https://doi.org/10.1021/op9000274