Wolff–Kishner reduction

The Wolff–Kishner reduction is a reaction used in organic chemistry to convert carbonyl functionalities into methylene groups. 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 and Ludwig Wolff in 1912.
Image:Wolff-Kishner-reaction scheme-new.png|class=skin-invert-image|center|420px|Scheme 1. Wolff-Kishner Reduction
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. 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 leads to formation of an alkylanion which can be protonated by solvent to give the desired product.
Image:Wolff-Kishner mechanism-s.png|class=skin-invert-image|center|900px|Scheme 1-1. Summary of mechanism of Wolff-Kishner reaction
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 in 1911 and Ludwig Wolff in 1912. Kishner found that addition of pre-formed hydrazone to hot potassium hydroxide containing crushed platinized porous plate led to formation of the corresponding hydrocarbon.
Image:Kishner1.png|class=skin-invert-image|center|340px|Scheme 2. Kishner's conditions
Wolff later accomplished the same result by heating an ethanol solution of semicarbazones or hydrazones in a sealed tube to 180 °C in the presence of sodium ethoxide.
Image:Wolff-new.png|class=skin-invert-image|center|550px|Scheme 3. Wolff's conditions
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. 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. According to Szmant's research, the first step in this reaction is the formation of a hydrazone anion 1 by deprotonation of the terminal nitrogen by MOH. If semicarbazones are used as substrates, initial conversion into the corresponding hydrazone is followed by deprotonation. A range of mechanistic data suggests that the rate-determining step involves formation of a new carbon–hydrogen bond at the carbon terminal in the delocalized hydrazone anion. This proton capture takes place in a concerted fashion with a solvent-induced abstraction of the second proton at the nitrogen terminal. Szmant’s finding that this reaction is first order in both hydroxide ion and ketone hydrazone supports this mechanistic proposal. Several molecules of solvent have to be involved in this process in order to allow for a concerted process. A detailed Hammett analysis 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.
The final step of the Wolff–Kishner reduction is the collapse of the dimide anion 2 in the presence of a proton source to give the hydrocarbon via loss of dinitrogen to afford an alkyl anion 3, 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. The overall driving force of the reaction is the evolution of nitrogen gas from the reaction mixture.
Image:Wolff-Kishner mechanism-new.png|class=skin-invert-image|center|620px|Scheme 4. Mechanism of the Wolff-Kishner reduction

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. 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.

	Original procedure	Huang Minlon	Barton	Cram	Henbest	Caglioti	Myers
Reagents	carbonyl compound, 100% H₂NNH₂, Na or NaOEt	carbonyl compound, 85% H₂NNH₂, KOH	carbonyl compound, anhydrous H₂NNH₂, Na	preformed hydrazone, KOtBu	preformed hydrazone, KOtBu	tosylhydrazone, hydride donor	carbonyl compound, 1,2-bis- hydrazine, Sc₃, KOtBu
Solvent	high-boiling solvent, e.g. ethylene glycol	high-boiling solvent, e.g. ethylene glycol	high-boiling solvent, e.g. diethylene glycol	anh. DMSO	toluene	THF	DMSO
Temperature	200 °C	180–200 °C	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	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- 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. 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-propionic acid to γ-butyric acid in 95% yield compared to 48% yield obtained by the traditional procedure.
Image:Huang-Minlon modification.png|class=skin-invert-image|center|650px|Scheme 5. Huang Minlon modification

Barton modification

Nine years after Huang Minlon’s first modification, Barton developed a method for the reduction of sterically hindered carbonyl groups. 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.
Image:Barton1.png|class=skin-invert-image|center|600px|Scheme 6. Barton modification