Over the past few tutorials, we’ve examined a variety of pericylic reactions.
First we looked at [4 + 2] cycloadditions like the Diels-Alder reaction.
This is where two separate molecules come together to form a cyclic compound by the
generation of two new sigma bonds.
Then we looked at [3,3] sigmatropic shifts, where a single sigma bond is broken and reformed
in a new location via a pi cloud.
Now let’s look at something called a 6-electron electrocyclization.
This is where a new ring forms in intramolecular fashion, by the production of one sigma bond
and loss of one pi bond.
An example is shown here involving 1,3,5-hexatriene, where the three pi bonds shuffle to form two
pi bonds and one new sigma bond, thus generating a six-membered ring.
Like the other pericyclic reactions we’ve discussed, electrocyclizations are reversible,
which means that electrocyclic ring opening is also possible.
Normally the equilibrium lies towards ring formation, because a pi bond is replaced with
a stronger sigma bond.
Now let’s talk about stereochemistry.
We saw that there are stereochemical rules that govern cycloadditions as well as sigmatropic
shifts, and electrocyclizations are no different.
The stereochemistry of these can be explained using frontier orbital theory, which we won’t
dive into very deeply, but we can go over a few key points that will give us some important
guidelines and new terminology.
This can be done by looking at just two examples.
First, let’s examine another 6-electron cyclization, this time with two R groups on
the terminal carbons of the starting material, which is an E, Z, E triene.
There is a rule that says for such a [4 + 2] electrocyclization, in order for the new
sigma bond to form, the termini of the triene must rotate in disrotatory fashion.
This means that the p orbitals on these carbons will rotate in opposite directions in order
to generate the in-phase direct overlap that will form the new sigma bond.
In doing so, the two substituents will both get pushed up to occupy these wedge bonds,
so they end up cis to one another on the product.
If the triene were E, Z, Z, then the substituents would end up trans to one another on the product.
And if the central double bond is E, no cyclization can take place.
So that covers 6-electron cyclizations.
Now let’s look at 4-electron cyclizations.
These are less common because of the anti-aromatic character of the transition state and the
ring strain associated with four-membered rings, but they are possible.
Consider the situation with this E,E-diene.
This time, in order to get in-phase direct overlap to produce the new sigma bond, the
termini of the diene must rotate in conrotatory fashion.
This means they both rotate in the same direction.
This leaves us with a trans cyclobutene, though once again, the equilibrium lies closer to
the reactant than the product.
We can actually take advantage of the direction of this equilibrium to do interesting chemistry.
Take the cyclobutene we just formed.
This can certainly go the other way to generate the diene, and dienes react with dienophiles
in Diels-Alder reactions.
This means that we can react this cyclobutene with something like maleic anhydride, and
as electrocyclization takes place to produce the diene, it will immediately react in Diels-Alder
fashion.
The stereospecificity is determined first by the conrotatory fashion in which the sigma
bond initially breaks, and then by the fact that the resulting diene will react with the
dienophile in endo fashion.
But that’s not all, we can push this quite a bit further.
Now consider this tetraene, reacting again with maleic anhydride.
Working first with the tetraene, given the 8 pi electrons, this must behave like the
4 electron system we saw earlier, so this will cyclize in conrotatory fashion to give
the following eight-membered ring.
However, this can cyclize further.
Now with 6 pi electrons, this will react in disrotatory fashion to generate a new six-membered
ring with two pi bonds, which is fused to a four-membered ring.
Now that we have a diene, this can finally react with maleic anhydride in a Diels-Alder
reaction, generating the endo product, which is this rather complex polycyclic structure
here.
So as you can see, we just performed a double electrocyclization/Diels-Alder cascade.
That’s three reactions that happen in rapid succession to yield this product.
But the most impressive aspect is the stereoselectivity.
All eight of the chiral centers on the product are determined by the rules associated with
these reactions, making this a useful technique.
Lastly, we are not limited to six-membered rings, we can generate five-membered rings
as well.
An important example of this is called the Nazarov cyclization.
This involves strong acid, and we can see the ring that forms as a result.
Looking at the mechanism will help elucidate this.
First, we know that strong acids can protonate carbonyls.
So let’s push the pi bond on the carbonyl up onto the oxygen to neutralize it, leaving
a formal positive charge on the adjacent carbon.
This will prompt the cyclization, with one pi bond going to form the new sigma bond,
and the other pi bond neutralizing the carbocation.
This step is done in conrotatory fashion.
Then elimination can occur, followed by tautomerization from the enol to keto form, in order to leave
us with the cyclopentenone product.
So even with just this handful of electrocyclizations we have introduced, we are beginning to see
what a powerful synthetic tool this is.
By using a variety of substrates and charges we can produce rings of different sizes, often
with strong stereoselectivity, something which is invaluable in the laboratory.
And that concludes our survey of pericyclic reactions.