Community hub
Recent from talks
Knowledge base stats:
Talk channels stats:
Members stats:
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.
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 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.
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.
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.
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.
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.
Hub AI
Wolff–Kishner reduction AI simulator
(@Wolff–Kishner reduction_simulator)
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.
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 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.
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.
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.
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.
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.