Earlier in the series we learned about Clemmensen reduction, which is a way to reduce aldehydes and
ketones all the way down to the alkane, thereby removing an oxygen atom entirely. This is
performed in the presence of zinc and hydrochloric acid. However, there is an alternative method that
will achieve this transformation under basic conditions, which can be a useful technique,
and this is called Wolff-Kishner reduction. This method, which actually was developed first,
was articulated independently in 1911 and 1912 by German chemist Ludwig Wolff
and Russian chemist Nikolai Kishner. The transformation was carried out with hydrazine
and a strong base like potassium hydroxide at very elevated temperatures in a high-boiling solvent,
such as ethylene glycol, which refluxes at 197oC, or even diethylene glycol, which boils at 245oC.
So how is this achieved? The mechanism first involves the formation of a hydrazone.
We have seen these types of condensation reactions before, which proceed with elimination of water,
so beyond stating that one of these nitrogen atoms attacks the carbonyl,
we don’t really need to illustrate this in detail. It is actually sometimes advantageous
to pre-form the hydrazones, since they are usually stable, crystalline compounds,
and the yield is often better if this first step is followed by an isolation. Alternatively,
if going all at once, the water formed in the condensation should be distilled off.
Now, hydrazones are in equilibrium with a tautomeric form, the diimide,
and this equilibration is catalyzed by base. Notice the additional proton on
this carbon in the diimide tautomer, as well as the double bond between the nitrogens.
Then, the slow step for this reaction is the deprotonation of the diimide by the strong
base. This leads to loss of nitrogen gas and the formation of a carbanion, which is an especially
reactive species. The lifetime of a carbanion in a protic solvent is extremely short, and
protonation by the conjugate acid of the base used in the previous step leads directly to the alkane.
Given the utility of this transformation in synthesis, this method has been used often
and it is still used today. It has been used on ton scale for the synthesis of pharmaceuticals,
although liquid hydrazine, which is also used in rocket fuels,
is a hazardous reagent at such high temperatures and must be handled by
experts, as it detonates in the gas phase even in the absence of oxygen.
Given the drastic conditions used in the original Wolff-Kishner protocol, it is not surprising that
many workers have endeavored to develop milder conditions, and this has given rise to a host of
modifications of the reaction. A complete survey of all the methods inspired by Wolff
and Kisher’s original work is beyond the scope of this tutorial. However, just to give you a
flavor of where modern synthesis can lead, let’s mention the improvement made in 1962 by American
chemist Donald Cram, Nobel Prize winner for his work in supramolecular chemistry. His group found
that if you use potassium tert-butoxide as a base and dimethyl sulfoxide as the solvent,
these are exceptionally basic conditions and the reaction can then be run at room temperature.
There are other modifications which now allow the use of this reaction even on sensitive substrates.
To show you an example of a complex strategy involving Wolff-Kishner reduction,
suppose you have to carry out the following transformation, the alkylation of pyrrole at
this particular carbon. It turns out that this is a difficult operation. You may suggest a
Friedel-Crafts alkylation, but this does not work cleanly, and one obtains a mixture of two isomers
plus dialkylated products. Conditions to do this cleanly have not been found. However,
it turns out that pyrrole 2-carboxylic acid is readily available, and this can be converted for
protection to the ethyl thioester by simple means. These thioesters were shown to be excellent
substrates for Friedel-Crafts acylation, though not alkylation,
at C-4. The reaction occurs exclusively at that position. The reason for this is easy to see
by drawing the Wheland intermediates leading to all the three possible isomeric products.
Of the three isomeric intermediates, A and C place a positive charge next to the electron-withdrawing
thioester group, and are therefore disfavored, whereas isomer B has the positive charge
in a position that is not conjugated with the thioester and is therefore much more stable.
Under Wolff-Kishner conditions, the acyl group at C-4 is reduced to an alkyl group, the thioester is
hydrolyzed to a carboxylic acid, and it is known that pyrrole 2-carboxylates readily decarboxylate,
so they lose CO2 under basic conditions, which leaves us with the desired product we mentioned
earlier. This three-step procedure is still the best way to prepare 3-alkyl pyrroles,
and it highlights the utility of the Wolff-Kishner reduction in situations where a carbonyl is
needed to carry out a specific transformation efficiently, but must then be removed to prepare
a target which is not accessible directly. Such strategies are common in organic synthesis. In
summary, the Wolff-Kishner reduction is still the most direct way to reduce ketones to alkanes,
and it is important for all organic chemists to be familiar with it.