A formylation is a reaction in which a formyl group is introduced to a compound, meaning
a CHO group, resulting in an aldehyde.
The formylation of electron-rich aromatic compounds with a mixture of dimethylformamide
and phosphorus oxychloride is commonly referred to as the Vilsmeier reaction, or sometimes
the Vilsmeier-Haack reaction, from the names of the two German chemists who first described
it in 1927.
The reaction consists essentially of a Friedel-Crafts-type process to form an iminium salt, followed
by hydrolysis to release the free aldehyde, and we will get a closer look at this mechanism
in a moment.
The reaction follows the typical reactivity and site-selectivity of any electrophilic
aromatic substitution, so in this case para site-selectivity is observed.
Other reagents can also be used in place of DMF, and other activators can be used as well,
like for example phosgene or phosphorus pentachloride, but liquid phosphorus oxychloride is convenient
to use and is the preferred reagent.
So let’s check out the mechanism.
In the first part, the Vilsmeier reagent is formed.
As we can see, nitrogen pushes its lone pair onto carbon, then oxygen attacks phosphorus,
and one of these chlorines will leave.
Because of this we now have chloride in solution, which will attack this carbon, and this carbon-oxygen
bond will cleave.
This is the Vilsmeier reagent.
Once formed, the reaction with the aromatic substrate takes place.
Electrophilic aromatic substitution takes place at this electrophilic carbon, neutralizing
the nitrogen, and yielding this intermediate.
Loss of a proton finishes up the EAS reaction.
Then nitrogen uses its lone pair to kick off chlorine, which leads to the iminium ion.
This can be isolated in some cases, especially if it crystallizes.
However, such intermediates are not stable to work up and they will readily hydrolyze.
This should be familiar, but just to be thorough, water attacks and neutralizes the nitrogen,
proton transfers occur, then a lone pair on oxygen kicks off the amine, one more proton
transfer, and we are left with the aldehyde, which is the product of the reaction.
The Vilsmeier reagent is a powerful electrophile, and one reason this reaction is still synthetically
important nearly a century after its development is that we are still exploring the range of
substrates that react with it, thus broadening the scope of this reaction.
For example, simple alkenes, such as these shown here, can react with a Vilsmeier reagent,
which we will understand to be present once these two reagents interact, as in the first
step in the mechanism we just went over.
In most cases, the reaction leads to formylation at the less substituted carbon, although these
reactions are not always high yielding, while also producing a mixture of E and Z isomers.
An interesting extension applies to carbonyl compounds, which can react at the active methylene
moieties via their enol forms.
Consider the following ketone, which can only enolize in one direction.
If the ketone can yield two different enols, usually the more substituted one forms, but
in this case we have just one option.
Attack of the reagent at the beta carbon of the enol yields the iminium ion, which is
in equilibrium with the conjugated enol.
This can actually react again with another Vilsmeier reagent, but because the beta carbon
of the enol is already heavily substituted, it reacts at the enol oxygen, yielding this
intermediate.
Then a chloride ion attacks this position on the unsaturated iminium, leading to expulsion
of one molecule of DMF.
And finally, after mild hydrolysis, the β-chloro-α,β-unsaturated aldehyde is achieved as a mixture of E and
Z geometric isomers.
Finally, we can examine the situation involving carboxylic acids.
Since carboxylates have an α-methylene group, a double formylation with accompanying decarboxylation
is observed.
Let’s look at a specific example.
The enol of phenyl acetic acid is probably the active nucleophile.
Reaction with the Vilsmeier reagent leads to the expected iminium ion.
This decarboxylates easily under acidic conditions, leading to the highly conjugated enamine.
This intermediate is quite nucleophilic, in fact more so than an enol, so it reacts again
with the Vilsmeier reagent to yield this mixed iminium/enamine product, which can be isolated
if necessary.
However, in situ hydrolysis leads to 2-phenyl malonic aldehyde, which can react in interesting
ways with a number of reagents.
For one useful example here, hydrazine smoothly condenses with the dialdehyde and leads to
4-phenyl pyrazole.
In this tutorial, we have only scratched the surface with the applications of the Vilsmeier
reagent.
Research continues today to find more interesting applications for this excellent electrophile
with a number of nucleophilic substrates.
Perhaps one day you can think of a new application yourself!