Next up in our survey of name reactions is the Passerini reaction. To delve into this reaction,
we first have to introduce an interesting new class of reactive compounds, the isonitriles,
also known as isocyanides. Be careful not to mix these up with isocyanates, which we have
discussed in other tutorials. Isonitriles are zwitterionic, with a positive charge
on the nitrogen and a negative charge on the adjacent carbon, and a triple bond between them.
Now, when reacting one equivalent of a primary formamide with a good dehydrating agent in the
presence of excess base, something interesting happens. First, the dehydrating agent, let’s say
an aryl sulfonyl chloride, reacts at the more basic center of the amide, the carbonyl oxygen,
and forms an imidoyl sulfonate. The nitrogen that initiated this step with its lone pair now has a
positive charge, so pyridine or a similar amine will act as a proton sponge to neutralize the
nitrogen, which is why this reaction requires a primary formamide rather than secondary, so
that a proton is present for this step to occur. The sulfonate is an excellent leaving group due
to resonance stabilization, so the reaction will proceed further. Just as with the previous step,
this nitrogen will push its lone pair onto carbon, and this time the sulfonate will leave,
leading to a protonated isonitrile. Given that pyridine is present in excess, this intermediate
is also deprotonated to yield the isonitrile. Now, isonitriles are the less stable structural
isomers of nitriles. As we can see, in nitriles, the CN group is bound to an R group through the
carbon atom. But in an isonitrile, the R group is bound via the nitrogen atom, so this totally
changes things in terms of electron distribution. Isonitriles can be represented two different ways.
Starting with the zwitterion, if one of the pi bonds in the triple bond is given to the nitrogen,
this will neutralize both atoms, leaving us with a carbene. Since these are both
simply resonance structures, recall that the reality lies somewhere in between.
Two questions may arise if you have been paying attention. Number one: If the isonitrile is so
much less stable than the nitrile, why does it not convert? The answer is that it does,
and the reaction has been studied both kinetically and thermodynamically.
We will not go over these studies in detail. Suffice it to say that,
although the reaction is spontaneous, meaning it has a negative delta G, the activation energy
for the process is very high. The R group has to effect a 1,2-migration, and this is accompanied by
severe distortions in the transition state. Thus, if you can form isonitriles at room temperature,
as with the above reaction, they are quite stable kinetically. They can even be isolated,
although they are well-known among chemists for their incredibly foul odor,
and thus are often used in situ, meaning formed and then used immediately without purification.
The stability of these unusual compounds illustrates the principle that,
for a reaction to occur readily, it must have both a favorable delta G and a low delta G of
activation. Due to their high delta G of activation, isonitriles are quite stable,
do not easily convert to nitriles, and display their own quite fascinating chemistry.
Indeed, this might be the second question: Do isonitriles react as carbenes, or as carbanions
from the zwitterionic form? Well, the answer is both. Their carbene nature affords them many
applications in cycloaddition chemistry, and they are important ligands in organometallic chemistry,
like all other carbenes. Here, however, we will deal with their reactivity as mild nucleophiles.
The first reaction of isonitriles we will discuss was invented by Italian chemist Mario Passerini in
1921. It is an example of a “multicomponent reaction”, in this case a reaction in which
three reactants combine to form a single product, an alpha-acyloxy amide. The reactants involved
are a carbonyl compound, such as a ketone or an aldehyde, a carboxylic acid, and an isonitrile.
Now let’s take a look at precisely how this works. The mechanism is most likely stepwise and first
involves the nucleophilic attack of the isonitrile onto the carbonyl compound,
the ketone in this case, which is first activated by protonation from the carboxylic acid.
This leads to a very electrophilic nitrilium ion, and even this carboxylate that results
from the previous proton transfer is nucleophilic enough to attack it. So here we see the oxyanion
attacking this carbon, which pushes a pi bond up to the nitrogen to neutralize it.
Now here is the interesting part. This intermediate undergoes
a 1,3-intramolecular shift of the acyl group to give the more stable alpha-acyloxy amide,
so in the end this is thermodynamically driven, and there is our product.
So what can we do with this kind of chemistry? The Passerini reaction is very popular in an area
of chemistry which deals with library synthesis. Often chemists make libraries of many compounds,
perhaps a few hundred or a few thousand, and screen them to see if, by sheer luck,
some of them have some desired chemical or biological properties. With current technologies,
a few thousand compounds can be screened in less than a day. In this reaction, one can vary four
substituent groups, two on the ketone, one on the carboxylic acid, and one on the isonitrile,
and it is therefore possible to reach a high level of diversity utilizing a single reaction.
For example, if one chooses ten readily available ketones and ten carboxylic acids,
and also makes ten isonitriles, all the possible combinations together
afford 1,000 compounds as potential products. Now, looking again at our generalized example,
if you are observant, you will notice that the reaction leads to a chiral product.
With the carbonyl group, if R1 does not equal R2, it is considered prochiral,
so the product has a stereogenic center, this one here that used to be the carbonyl carbon.
And since the reaction requires no activator or catalyst, the product will be racemic. It
turns out that for the synthesis of libraries, this is not a major concern. Once an active
compound has been picked up from a screen, the racemate can be easily deconvoluted,
meaning that the enantiomers are separated, usually by chromatography on a chiral support,
and the relative activity of each enantiomer can then be determined.
However, in the field of organic synthesis, racemates are very undesirable in the
21st century, given that we have so many enantioselective transformations. Thus, an
enantioselective version of the Passerini reaction would have great utility. This is currently a very
active area of research and initial results are encouraging. Many research groups have reported
enantioselective Passerini reactions exploiting the observation that Lewis acids catalyze this
reaction, and chiral Lewis acids can therefore be used to make the reaction enantioselective.
Among the many successful applications, we will refer to the work of Professor Jieping Zhu, at the
Polytechnic Institute in Lausanne, Switzerland. This time we are using this four-carbon aldehyde,
benzoic acid, and this particular isonitrile, leading again to an alpha-acyloxy amide. With this
particular example, the product is obtained in 84% enantiomeric excess, which means one obtains 92%
of this S enantiomer and only 8% of the R, using 10 mole percent of a chiral aluminum catalyst,
which has the structure shown here. Note that with the catalyst the reaction is now so fast
that it can be run at negative 40 degrees Celsius. The reaction works only for aldehydes, and within
this constraint, the ee ranges from 63 to 99% for a series of similar products. These results are
quite good but not yet completely satisfactory. Thus, the search for the ideal catalyst continues.
So as we can see, the 100-year old Passerini reaction is now more than ever the topic of
intense attention from the synthetic community, in their quest to create
a highly general enantioselective version of this intriguing three-component transformation.