The Nef reaction was reported by Swiss chemist Johann Nef in 1894. It involves
the hydrolysis of a nitronate salt to yield a carbonyl compound and nitrous oxide.
The reaction is general for primary nitronates, which yield aldehydes, and secondary ones, which
yield ketones. And in fact, the first reported example involved nitroethane to form acetaldehyde.
Although this is essentially a degradative reaction and not a skeleton-building reaction,
there is a reactivity aspect which makes the Nef reaction extremely useful.
Due to the high carbon acidity and nucleophilic reactivity of nitroalkanes,
the reaction can be incorporated into a strategy called “Umpolung”,
a German word introduced by Professor Dieter Seebach of ETH Zurich and U.S. Nobelist
E. J. Corey of Harvard University to designate a “reverse of polarity”. We will introduce the
Umpolung concept in this tutorial, to further elucidate the importance of the Nef reaction.
The accepted mechanism for the Nef reaction is as follows. We must preface this by stating
that alkyl nitro derivatives are rather acidic carbon acids. Their pKa of around 10 makes them
comparable to common oxygen acids like phenols or nitrogen acids like trialkyl ammonium ions.
This means we can make their salts with a strong base, like sodium hydroxide, and these salts are
even isolable. These are called nitronates and they are the starting point of the Nef reaction.
In a strongly acidic medium like 4 normal sulfuric acid, kinetic protonation occurs,
not at carbon to yield the starting nitroalkane again, but rather at the oxygen, yielding the aci
form, which is a tautomer of the nitroalkane in which a C-H bond has been replaced by an O-H bond.
This form is immediately protonated again at the other oxygen atom to yield
the conjugate acid of the nitroalkane. This looks a lot like an iminium salt,
which you may recall are easily hydrolyzed in water because they are very electrophilic.
Here, water is the only nucleophile, and attack of water over two steps leads to
loss of the nitrogen-containing fragment, which ultimately yields nitrous oxide gas and water.
We should be aware that the major side product in the Nef reaction is usually a hydroxamic acid,
which is an amide with a hydroxyl on the nitrogen. This is especially the case if more concentrated
sulfuric acid is used, around 10 molar. It appears likely that under these conditions,
the nitroalkane is doubly protonated, which means the nitronate is triply protonated, which leads
to a different pathway. Loss of a proton can occur from the carbon atom next to the nitrogen,
which yields a hydroxy nitrilium ion. This is rapidly hydrated to give the hydroxamic acid.
If conditions are extreme, this can even be hydrolyzed to give the carboxylic acid. Thus,
the Nef reaction must be run under well-calibrated acidic conditions to avoid side reactions.
Now let us get back to some important terminology. In the Nef reaction, nitroalkanes are Umpolung
reagents. An Umpolung reagent is one which allows us to carry out synthetic operations
through a reversal of polarity. For example, an aldehyde contains a carbonyl group which
is electrophilic and reacts rapidly with strong nucleophiles, like an enolate. After protonation
we get the aldol product, which should be very familiar from earlier in the series.
Thus, a carbonyl can act as an electrophile, whereas the carbon atom next to it is deprotonated
by strong bases and acts as a nucleophile. This is the normal, expected polarity.
Another operation, where the carbonyl carbon acts as a nucleophile would be called “reverse
polarity” and would be very hard to do directly. This is because it is quite difficult to produce
acyl anions and use them synthetically. If this were possible, the following reactions
could occur. These would result in either an alpha-hydroxycarbonyl or gamma-keto dicarbonyl
compound, as opposed to a beta-hydroxycarbonyl or delta-keto dicarbonyl compound which is obtained
using a normal-polarity reaction like the aldol condensation or Michael addition.
This is due to the fact that it would be the carbonyl carbon attacking
rather than the alpha carbon, and if this specific spatial arrangement for these functional groups
were desirable for a particular synthesis, it would be tremendously useful to be able
to achieve such a transformation. We can indeed perform transformations resembling these ones
through an Umpolung approach. This is what we mean by reversal of polarity.
By somehow causing the carbonyl carbon, which is usually electron-deficient and electrophilic,
to become electron-rich and nucleophilic, that would change the types of chemistry
it would be capable of doing and thus the types of products that could form.
Let us illustrate the Umpolung concept with the Michael addition of nitronates to enones.
An example is shown in the synthesis of cyclopentenones. Under basic conditions the
nitro compound forms the nitronate, which reacts with the enone, undergoing a Michael addition,
just as though this had been a regular enolate. The product can be treated with base to again
obtain the nitronate, which undergoes the Nef reaction under acidic conditions to give the
dione. Notice the resulting spatial relationship of these carbonyls, which is not what we would
expect had we used a ketone or aldehyde enolate rather than the nitronate. Now the 1,4-dicarbonyl
system can cyclize to give a cyclopentenone via an intramolecular aldol reaction.
Note that deprotonation will occur at the more acidic benzylic position due to resonance, and
this carbon will then attack the other carbonyl. After the condensation step and loss of water,
we are left with the cyclopentenone. This strategy, coupled with others which
attain similar transformations, are very valuable, because it is not easy to obtain a 1,4-dicarbonyl
compound, due to the irregular separation of the functional groups involved. Therefore the
Nef reaction, coupled with the nucleophilicity of the nitronate anion, offers easy access into
this class of compounds, and is therefore a valuable tool in modern organic synthesis.