For the past few tutorials we have been going over some important name reactions, and no
such list would be complete without the Mannich reaction, as this is a very important tool
for any synthetic chemist.
The reaction was invented in 1912 by German chemist Carl Mannich, and has been the subject
of intense study, extensions, and applications ever since.
In its early embodiment, the reaction utilizes three components, those being formaldehyde,
an enolizable ketone, and a secondary amine.
The reaction is usually catalyzed by a mineral acid such as hydrochloric acid, and will yield
a product like this, with both ketone and amine functionality.
This is an interesting reaction mechanistically, so let’s get into the mechanism now.
It is the case that enolizable ketones react rapidly with formaldehyde under either acidic
or especially basic conditions, as we know from learning about Aldol condensation earlier
in the series.
These reactions are difficult to control due to the extreme reactivity of formaldehyde,
and often result in multiple additions to the enolate or enol of the ketone, until the
alpha carbon can’t accommodate any more carbon-carbon bonds.
However, when formaldehyde is in the presence of a secondary amine, like dimethylamine,
and under acid catalysis, things are a bit different.
As we can see the amine attacks the carbonyl, the resulting hydroxyl is protonated by the
acid, and then dehydration takes place to form the iminium ion.
This is also quite reactive as an electrophile, but reacts only once with ketone enols, and
the reaction is usually quite clean.
Here we see the aldol-like reaction which occurs between the enol of the ketone and
the iminium ion from the first sequence, which will yield the product of the Mannich reaction.
The acid catalyzes the equilibration between ketone and enol, and although at equilibrium
the ketone is by far the predominant species, there is enough reactive enol present in solution
to drive the transformation.
Sometimes to make the reaction smoother, chemists preform salts like the iminium ion from before
with some counterion, and these are called Eschenmoser salts, after their discoverer,
the Swiss chemist Albert Eschenmoser.
These salts are often commercially available, although they are moisture sensitive and must
be handled under a nitrogen atmosphere.
So that covers the original, straightforward version.
What else can we do with this kind of chemistry?
One of the more interesting applications of the Mannich reaction is in the methylenation
of enolizable ketones.
The Mannich product from a moment ago can be alkylated with methyl iodide, and this
leads to a quaternary ammonium salt.
This moiety is a good leaving group, as we have learned in a previous tutorial, and treatment
with strong base leads to β-elimination and the formation of an α-methylene ketone.
So the Mannich reaction combined with subsequent alkylative fragmentation allows the introduction
of a methylene group at the alpha position of enolizable ketones.
Now for another application, Eschenmoser salts are very electrophilic, and do not react only
with ketone enolates, but also with enolates derived from esters, nitriles, nitro compounds,
and the like.
Even electron-rich aromatics are very common nucleophilic partners in Mannich-like reactions.
Here are some examples using phenols and indoles.
This application will remind the observant chemist of the Friedel-Crafts reactions we
learned about earlier in the series.
In this case, however, the electrophile does not require Lewis acid activation.
It is also important to note that the Mannich reaction can be extended to aldehydes other
than formaldehyde.
However, if the ketone is more substituted than a methyl ketone, several diastereomers
can occur.
Given that stereochemical control is of great concern, the attention of synthetic chemists
has been focused on technologies that may allow one to select a specific diastereomer,
and therefore render these reactions diastereoselective and even enantioselective.
This goal has been met with considerable success, and there are way too many examples available
for us to cover them all.
However, to show what fine level of control is possible with chiral catalysis, here is
an example of a selective reaction under rather simple conditions.
The amino acid S-proline is the catalyst responsible for the high level of stereocontrol.
In this reaction, the syn diastereomer dominates 90 to 10, and for the two possible forms the
dominant enantiomer is obtained in over 99% optical purity.
Given that the minor components comprising 10% of the yield are isomeric compounds and
therefore in principle separable from the target by column chromatography, this synthesis
allows for the preparation of an enantiomerically pure product.
This chemistry has been extended successfully to a number of systems using a wide array
of catalysts, and currently constitutes a very hot area of research.
But for our purposes, we now understand the basics regarding the Mannich reaction.