Much earlier in this series, we discussed the Diels-Alder reaction. This is an example of a
cycloaddition reaction, which is one subclass of a broader class of reactions called pericyclic
reactions. We will spend the next few tutorials going over all kinds of pericyclic reactions,
so to start from a familiar place, let’s revisit the Diels-Alder reaction and dig a little deeper.
Looking at the simplest possible Diels-Alder reaction, we have 1,3-butadiene and ethene which
react to generate cyclohexene. As we recall, any Diels-Alder reaction will follow this basic setup,
with a diene and a dienophile going to generate a six-membered ring with a pi bond. The mechanism
for this reaction is in stark contrast with just about any other reaction we have investigated.
Typically when a chemical reaction occurs, there is some electron-rich species that interacts with
an electron-poor species, like when a nucleophile attacks an electrophile, or an acid-base reaction.
But here we see no such things. There are no polar bonds, and there is no intermediate,
the reactants combine through a simple transition state with no charges or dipoles.
This is a thermodynamically driven reaction, based on the stability of sigma bonds over pi bonds,
given that three pi bonds go to form one pi bond and two sigma bonds, which occurs
under appropriate thermal activation, meaning above a certain temperature. In displaying
this mechanism, we must understand that these arrows are not to be interpreted literally,
the pi electron density does not cyclize in a specific direction. The pi bonds dissipate as
the new bonds materialize in concerted fashion. We should also understand that the Diels-Alder
reaction is a [4 + 2] cycloaddition. This means that the diene contributes four pi electrons and
the dienophile contributes two, and these six pi electrons that are involved in the cyclization,
these are the electrons that are delocalized in the transition state.
We could then wonder what other types of cycloadditions are possible. Can we do [2 + 2],
or [4 + 4] as well? We could imagine ethene reacting with itself to form cyclobutane.
Or this diene reacting with itself to produce this cyclooctadiene. But in fact, these reactions do
not occur thermally. This is quite good, as otherwise, the Diels-Alder reaction between
these compounds would yield a messy mixture of products. In fact, if 1,3-butadiene is forced
to react with itself under extreme conditions, it will still perform a [4 + 2] cycloaddition to give
this Diels-Alder product, breaking the conjugation of the diene in the process, but never a [4 + 4].
So what is it about the [4 + 2] combination that works, where the others don’t? Much
like many other chemical phenomena, the explanation involves molecular orbitals.
We did touch on this in the introductory tutorial regarding Diels-Alder reactions, and we understood
that in order for the highest occupied molecular orbital of the diene to put electron density into
the lowest unoccupied molecular orbital of the dienophile, the relevant overlapping orbitals must
be in-phase with one another as the reactants approach one another in vertical fashion.
With four pi electrons in the diene, that makes this the HOMO, with one node, and with two pi
electrons in the dienophile, that makes this the LUMO, again with one node. Therefore, it simply
happens to be the case that this in-phase overlap is possible with [4 + 2], while it does not work
for the other two configurations we discussed. We could get much more in-depth than this,
but for now it will suffice to say that due to this orbital overlap, the transition state of
a [4 + 2] cycloaddition has some aromatic character, which is a stabilizing feature,
and a more stable transition state means a lower activation energy, and therefore a more favorable,
or faster reaction. We can therefore see how the transition states of the other configurations
prohibit those reactions, as Huckel’s rule for aromaticity is 4n + 2. Benzene works, but things
like cyclobutadiene and cyclooctatetraene do not. Instead they are anti-aromatic,
which is actually a destabilizing feature, just in the way that aromaticity is stabilizing.
So if we were to try to perform [2 + 2] or [4 + 4] cycloadditions, they would have to
surpass anti-aromatic transition states, which is highly energetically unfavorable.
But what this also means is that other cycloadditions with transition states that
satisfy Huckel’s rule are also feasible. For example, [6 + 4] cycloadditions are
acceptable. Take the following example, with this seven-membered ring and our familiar butadiene.
We get a new ten-membered ring instead of the usual six with the Diels-Alder, which
does not have tremendous utility in synthesis, but is a fascinating possibility nonetheless.
Returning to the Diels-Alder reaction, let’s recall some other aspects that will be
relevant as we move forward with pericyclic reactions. The reaction is stereospecific.
Whatever the stereochemistry of the dienophile, that will be retained in the product.
If a cis alkene, the substituents will be cis in the product. If a trans alkene,
then trans in the product. We can say something similar about substituents on carbons 1 and 4
of the diene. If in this orientation, they end up cis on the product, if in this orientation, they
will be trans to one another. We also mentioned something about the kinetics of the reaction.
The most favorable configuration is a diene with one or more electron-donating substituents,
like alkyl, hydroxyl, alkoxy, or amino, and a dienophile with one
or more electron-withdrawing substituents, like carbonyl-containing functional groups.
However, placing these substituents on the reactants also brings up questions regarding
regiochemistry, as the reactants can approach one another from either face, being planar molecules.
Consider a substituent in the 1-position on the diene and a monosubstituted dienophile.
The preference will be for these substituents to end up adjacent in the product. If, however,
the substituent on the diene is at the 2-position, the substituents will tend to end up directly
opposite one another in the product. Again, this is due to details regarding molecular orbitals,
but for now it will suffice for us to simply be aware of this regioselectivity. As a final detail,
let’s consider the stereochemistry associated with the first of the two products we just
mentioned. As you can see, we neglected to report any stereochemistry for the moment, though we must
acknowledge that these are both sp3 carbons, which means that a number of diastereomers are possible.
The question then becomes, is there any selectivity at play here? There actually is,
and we have briefly touched on endo vs. exo transition states before as well. Consider
the diene lowering down onto the dienophile. Remember, this is the orientation that must occur
so as to allow for the overlap of the orbitals that project in perpendicular fashion with respect
to the plane of each molecule. If the ester is eclipsed under the pi system of the diene, we get
the endo transition state. If projecting away, we get the exo transition state. In each case,
the new sigma bonds that will materialize are alluded to with the dashed lines. As it turns out,
the endo transition state is kinetically favored due to secondary orbital interactions between
the ester and the pi system on the diene that lower the activation energy of the reaction.
This favorability is about 3 to 1 in favor of the endo transition state, which will lead us
to expect a predominance of the endo product, and will result in these substituents being cis to one
another, as opposed to trans in the exo product. This is actually of remarkable use in synthesis,
not just because we are generating a six-membered ring, which is ubiquitous in natural products,
but also because of the stereospecificity and complexity produced with no reagent waste. There
are no leaving groups, no catalysts, it’s just two fragments that join together under thermal
activation. For this reason, this reaction is an indispensable tool for any synthetic chemist.
So once again, while most of this information had been covered in an earlier tutorial,
it will be important to cement this knowledge now, so that we may move forward
and take a look at some other pericyclic reactions that follow these principles,
but with some key differences that allow us to expand our grasp of synthetic methodology.