Next up in our survey of name reactions is the Ritter reaction.
This one is named after John Ritter.
No wait, not the John Ritter who played Jack Tripper from Three’s Company.
We are talking about American chemist John Ritter, who reported his earliest results
in 1948.
It is an interesting reaction that achieves the hydration of a nitrile to an amide, with
alkylation of the amide nitrogen by an alcohol.
The products of this reaction are amides, which can be hydrolyzed to yield primary amines.
This therefore indirectly constitutes a method to transform an alcohol into an amine.
The reaction works best for tertiary alcohols, but can be applied to secondary and primary
alcohols as well.
The water is usually added at the end, to quench the reaction.
For tertiary alcohols, the mechanism is assumed to proceed as follows.
First, the alcohol is protonated by the strong acid, which releases water and forms a tertiary
carbocation.
We know that carbocation stability follows the order tertiary > secondary > primary,
so this is also their order of reactivity in the Ritter reaction.
We have also seen that they tend to undergo isomerization via things like 1,2 hydride
or methanide shifts, and this is also a potential side pathway in the Ritter reaction.
The carbocation is attacked by the nitrile via the lone pair on the nitrogen, forming
a nitrilium ion, and this can be written as the sum of two resonance structures.
This intermediate is very electrophilic, and water will attack this carbon to form the
amide.
Now, we also know that stable carbocations can be obtained by protonation of highly substituted
olefins, also known as alkenes, and indeed another formulation of the Ritter reaction
operates via olefins as substrates as follows.
Again, the key intermediate is the carbocation, which is attacked by the nitrile, to produce
the expected amide product.
And as we mentioned, hydrolysis of the amide can yield the primary amine.
Of course, the Ritter reaction is not the main technique for making primary amines.
We have already discussed other approaches, such the Gabriel reaction.
However, Ritter’s original observation can be extended to modified applications that
have a lot of value in organic synthesis.
From this preliminary presentation, it will be easily understood that a nitrile can be
a good nucleophile for carbocations, and there are many ways to generate these intermediates.
Thus, instead of dehydrating an alcohol, we can use another method to generate a carbocation
in the presence of a nitrile, and in principle we may then produce useful extensions of the
Ritter reaction.
Let’s examine a few examples that just scratch the surface of the potential this reaction
may have.
The drug Crixivan, introduced by Merck, was one of the first effective drugs against AIDS,
and in the 1990s it attracted a huge amount of attention.
Its structure is quite complex, and organic chemists were facing a tremendous challenge
in trying to prepare ton amounts of the drug.
The molecule contains five stereogenic centers.
Two of them are located in what was called the aminoindanol subunit, highlighted here
in red.
Therefore, one of the key problems was figuring out how to prepare this subunit in high regiochemical
and stereochemical purity.
One intermediate that was available in good enantiomeric purity was this indene epoxide,
available from indene through enantioselective epoxidation, a reaction we will discuss in
a future tutorial.
The problem thus became: How do we go from this epoxide to the corresponding aminoindanol
with regio and stereocontrol?
The Merck chemists thought that the Ritter reaction would be a good candidate.
The epoxide would open up to form a carbocation under acidic conditions.
Of the two possible carbocations, this one seemed favored over the other because it is
a benzylic carbocation, and is thus stabilized by delocalization onto the benzene ring.
It turns out that they were right, and the amination occurs only at the benzylic position,
so the regiochemistry is all set.
The other question was about the stereochemistry.
If the amination is to be carried out with acetonitrile and subsequent hydrolysis, would
the acetonitrile attack from the same face as the hydroxyl, which is the desired outcome,
or the opposite face?
It turns out that the attack was only carried out from the same side as the alcohol, allowing
the isolation of this oxazoline, which can then be hydrolyzed to give the desired product
in very high yield.
So where does the stereoselectivity come from?
It turns out that the attack of the nitrile onto the carbocation, or the formation of
the nitrilium ion, is reversible.
And when we operate in the absence of water, there are no nucleophiles to capture the nitrilium
ion other than the adjacent hydroxyl group.
If the trans nitrilium ion is formed, attack is hindered because of the strain that would
result, since the groups are on opposite sides of the ring.
The cis nitrilium ion, on the other hand, quickly and irreversibly snaps shut to form
the oxazoline due to the proximity of the groups, and that is how the problem was solved.
We will finish up with a more advanced application, which was just published in 2021 by Professor
Babak Borhan at Michigan State University.
The goal was the amidochlorination of certain olefins with complete enantio- and regiocontrol,
and this example here works particularly well.
The plan is to create a chiral chlorenium ion, as is shown here, by the addition of
a chlorenium ion source to the olefin from the stereoface dictated by a chiral ligand.
This chiral chlorenium ion would then be the source of the carbocation for acetonitrile
to attack.
The chlorinating agent that worked best was dichloro dimethyl hydantoin, or DCDMH.
Attack of the acetonitrile anti to the chlorine atom at the carbon yielding the more stable
carbocation would lead to the product.
The idea worked perfectly well.
The ideal catalyst was found by screening, and it turned out to be (DHQD)2PHAL, a derivative
of quinine, and this yielded 98-99% e.e. for most substrates, which means complete enantioselectivity.
The regioselectivity was also essentially complete, and only one isomer out of four
possible ones was obtained in high yield.
The amount of catalyst required was only 1 mole percent.
This example brings us to the state of the art in Ritter chemistry.
As you can see, chemists can now combine old reactions with new methodologies, such as
enantioselective organocatalysis, to execute sophisticated, highly selective operations.
The field of enantioselective organocatalysis was recently recognized with the Nobel Prize
for chemistry to Professors List and McMillan.
Thus, even today the Ritter reaction continues to inspire chemists at the forefront of science
to create new useful reactivities and products.