carbonyl functionalities into methylene groups.[1][2] In the context of complex molecule synthesis, it is most frequently employed to remove a carbonyl group after it has served its synthetic purpose of activating an intermediate in a preceding step. As such, there is no obvious retron for this reaction. The reaction was reported by Nikolai Kischner in 1911[3] and Ludwig Wolff in 1912.[4]
In general, the reaction mechanism first involves the in situ generation of a hydrazone by condensation of hydrazine with the ketone or aldehyde substrate. Sometimes it is however advantageous to use a pre-formed hydrazone as substrate (see modifications). The rate determining step of the reaction is de-protonation of the hydrazone by an alkoxide base to form a diimide anion by a concerted, solvent mediated protonation/de-protonation step. Collapse of this alkyldiimide with loss of N2[2] leads to formation of an alkylanion which can be protonated by solvent to give the desired product.
Because the Wolff–Kishner reduction requires highly basic conditions, it is unsuitable for base-sensitive substrates. In some cases, formation of the required hydrazone will not occur at sterically hindered carbonyl groups, preventing the reaction. However, this method can be superior to the related Clemmensen reduction for compounds containing acid-sensitive functional groups such as pyrroles and for high-molecular weight compounds.
History
The Wolff–Kishner reduction was discovered independently by N. Kishner[3] in 1911 and Ludwig Wolff in 1912.[4] Kishner found that addition of pre-formed hydrazone to hot potassium hydroxide containing crushed platinized porous plate led to formation of the corresponding hydrocarbon. A review titled “Disability, Despotism, Deoxygenation—From Exile to Academy Member: Nikolai Matveevich Kizhner” describing the life and work of Kishner was published in 2013.[5]
Wolff later accomplished the same result by heating an ethanol solution of
hydrazones
in a sealed tube to 180 °C in the presence of sodium ethoxide.
The method developed by Kishner has the advantage of avoiding the requirement of a sealed tube, but both methodologies suffered from unreliability when applied to many hindered substrates. These disadvantages promoted the development of Wolff’s procedure, wherein the use of high-boiling solvents such as ethylene glycol and triethylene glycol were implemented to allow for the high temperatures required for the reaction while avoiding the need of a sealed tube.[6][7] These initial modifications were followed by many other improvements as described below.
Mechanism
The mechanism of the Wolff–Kishner reduction has been studied by Szmant and coworkers.
of aryl aldehydes, methyl aryl ketones and diaryl ketones showed a non-linear relationship which the authors attribute to the complexity of the rate-determining step. Mildly electron-withdrawing substituents favor carbon-hydrogen bond formation, but highly electron-withdrawing substituents will decrease the negative charge at the terminal nitrogen and in turn favor a bigger and harder solvation shell that will render breaking of the N-H bond more difficult. The exceptionally high negative entropy of activation values observed can be explained by the high degree of organization in the proposed transition state.
It was furthermore found that the rate of the reaction depends on the concentration of the hydroxylic solvent and on the cation in the alkoxide catalyst. The presence of crown ether in the reaction medium can increase the reactivity of the hydrazone anion 1 by dissociating the ion pair and therefore enhance the reaction rate.[11]
The final step of the Wolff–Kishner reduction is the collapse of the diimide anion 2 in the presence of a proton source to give the hydrocarbon via loss of dinitrogen to afford an alkyl anion3, which undergoes rapid and irreversible acid-base reaction with solvent to give the alkane. Evidence for this high-energy intermediate was obtained by Taber via intramolecular trapping. The stereochemical outcome of this experiment was more consistent with an alkyl anion intermediate than the alternative possibility of an alkyl radical.[13] The overall driving force of the reaction is the evolution of nitrogen gas from the reaction mixture.
Modifications
Many of the efforts devoted to improve the Wolff–Kishner reduction have focused on more efficient formation of the hydrazone intermediate by removal of water and a faster rate of hydrazone decomposition by increasing the reaction temperature.[6][7] Some of the newer modifications provide more significant advances and allow for reactions under considerably milder conditions.
The table shows a summary of some of the modifications that have been developed since the initial discovery.
180–200 °C (after removal of water and excess hydrazine)
210 °C
25 °C
111 °C
66 °C
25 °C
Advantages
single step procedure
reduced reaction times, higher temperatures can be reached, no need to use anh. hydrazine
allows decarbonylation of sterically hindered substrates
proceeds at room temperature
no slow addition of hydrazone necessary
mild reaction conditions, possible with a variety of reducing agents
very mild reaction conditions
Disadvantages
long reaction times (50–100 h)
distillation necessary
harsh reaction conditions
isolation of hydrazone and slow addition necessary
isolation of hydrazone necessary
isolation of tosylhydrazone necessary. hydride donor may act as base
synthesis of 1,2-bis(tert-butyldimethylsilyl)- hydrazine necessary
Functional group tolerance
does not tolerate esters, amides, halogens, cyano-, and nitro-groups
similar to original procedure
similar to original procedure
tolerates amides
higher tolerance of α-substituents that would undergo elimination and α,β-unsaturated enones that would undergo migration under original conditions
tolerates esters, amides, cyano-, nitro- and chloro-substituents with NaBH3CN as hydride source, does not tolerate primary bromo- and iodo-substituents
not reported
Huang Minlon modification
In 1946, Huang Minlon reported a modified procedure for the Wolff–Kishner reduction of ketones in which excess hydrazine and water were removed by distillation after hydrazone formation.[14][20] The temperature-lowering effect of water that was produced in hydrazone formation usually resulted in long reaction times and harsh reaction conditions even if anhydrous hydrazine was used in the formation of the hydrazone. The modified procedure consists of refluxing the carbonyl compound in 85% hydrazine hydrate with three equivalents of sodium hydroxide followed by distillation of water and excess hydrazine and elevation of the temperature to 200 °C. Significantly reduced reaction times and improved yields can be obtained using this modification. Minlon's original report described the reduction of β-(p-phenoxybenzoyl)propionic acid to γ-(p-phenoxyphenyl)butyric acid in 95% yield compared to 48% yield obtained by the traditional procedure.
Barton modification
Nine years after Huang Minlon’s first modification, Barton developed a method for the reduction of sterically hindered carbonyl groups.[15] This method features rigorous exclusion of water, higher temperatures, and longer reaction times as well as sodium in diethylene glycol instead of alkoxide base. Under these conditions, some of the problems that normally arise with hindered ketones can be alleviated—for example, the C11-carbonyl group in the steroidal compound shown below was successfully reduced under Barton’s conditions while Huang–Minlon conditions failed to effect this transformation.
Cram modification
Slow addition of preformed hydrazones to potassium tert-butoxide in DMSO as reaction medium instead of glycols allows hydrocarbon formation to be conducted successfully at temperatures as low as 23 °C.[16] Cram attributed the higher reactivity in DMSO as solvent to higher base strength of potassium tert-butoxide in this medium.
This modification has not been exploited to great extent in organic synthesis due to the necessity to isolate preformed hydrazone substrates and to add the hydrazone over several hours to the reaction mixture.
Henbest modification
Henbest extended Cram’s procedure by refluxing carbonyl hydrazones and potassium tert-butoxide in dry toluene.[17] Slow addition of the hydrazone is not necessary and it was found that this procedure is better suited for carbonyl compounds prone to base-induced side reactions than Cram's modification. It has for example been found that double bond migration in α,β-unsaturated enones and functional group elimination of certain α-substituted ketones are less likely to occur under Henbest's conditions.[21]
Caglioti reaction
Treatment of tosylhydrazones with hydride-donor reagents to obtain the corresponding alkanes is known as the Caglioti reaction.[18][22] The initially reported reaction conditions have been modified and hydride donors such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catecholborane can reduce tosylhydrazones to hydrocarbons.[23] The reaction proceeds under relatively mild conditions and can therefore tolerate a wider array of functional groups than the original procedure. Reductions with sodium cyanoborohydride as reducing agent can be conducted in the presence of esters, amides, cyano-, nitro- and chloro-substituents. Primary bromo- and iodo-substituents are displaced by nucleophilic hydride under these conditions.
Thereduction pathway is sensitive to the pH, the reducing agent, and the substrate.
inductive effects. The transient azohydrazine 4 can then be reduced to the tosylhydrazine derivative 2 and furnish the decarbonylated product analogously to the first possibility. This mechanism operates when relatively weak hydride donors are used, such as sodium cyanoborohydride. It is known that these sodium cyanoborohydride is not strong enough to reduce imines, but can reduce iminium