{getToc} $title={Table of Contents}
Introduction
In this article, we will be discussing a few things, namely cycloaddition reactions (such as the Huisgen 1,3-dipolar cycloaddition), particularly the Diels-Alder reaction, as well as the Woodward-Hoffmann rules. Before we begin looking into the types of cycloaddition reactions, we must understand what they are in the first place. Simply stated, they are a special type of addition reaction which involves the formation of a cyclic compound - that explains the name of this article, ‘forming circles’.
Cycloaddition reactions are useful ways to form cyclic compounds from straight-chain molecules. To illustrate cycloaddition reactions, we will begin with an unusual example, which is of the formation of aziridines (Fig. 1), known as azide-alkyne Huisgen cycloaddition. Two mechanistic pathways have been suggested, but only the first and more widely accepted one will be discussed.
Fig. 1: Azide-alkyne Huisgen cycloaddition.
In this mechanism, the first step involves a 1,3-dipolar addition. This means that the two terminal nitrogen atoms of the azide add to adjacent carbon atoms resulting in the formation of a cyclic five-membered ring, otherwise known as triazoline. Finally, radical facilitation is used to effect a ring contraction, resulting in the aziridine.
The 1,3-dipolar addition itself is an interesting chemical transformation that deserves to be discussed further. This is technically a cycloaddition reaction, specifically a [4 + 2]-cycloaddition (Fig. 2). As we have not yet discussed the nomenclature of cycloaddition reactions, we will briefly note it here.
Fig. 2: Mechanism of Huisgen cycloaddition (1,2-addition).
Simply, a [4 + 2]-cycloaddition suggests that there are four electrons from one molecule and two electrons from another molecule participating in the cycloaddition. In the case of aziridine formation, the molecule with four participating electrons is the azide while the molecule with two participating atoms is the alkene.
For this addition to occur, one of the atoms has to possess a lone pair while the other has to possess a vacant orbital. Because of this, it is common for atoms to have point charges and therefore resonance forms to stabilize these point charges.
The first case is of the molecule a--b=c+, which features two point charges. It has a resonance form where a triple bond is present. The second case is of the molecule a--b-c+-, where resonance allows for only the double bond and not the triple bond to form.A variation of this reaction comes from the possibility of 1,4-addition in place of 1,2-addition, a theme that we have already discussed for conjugated dienes in a previous article. For those who do not know the mechanism of a 1,4-addition, the article is a good read. So, a little quiz: what type of cycloaddition would the 1,4-addition variation be?
Well, the answer is that it is a [4 + 4]-cycloaddition (Fig. 3). Remember, in the [4 + 2] case, we only had to consider one double bond, and the movement of that single double bond only affects two atoms. In the 1,4-addition case, both double bonds are touched and will be affected, meaning more atoms will be affected.
Fig. 3: Mechanism of aziridine formation (1,4-addition).
Since the azide will only involve the movement of 2 electrons, the number will remain the same, being just 2. However, since four electrons instead of two are affected in the 1,4-addition (refer to Fig. 3), the second number will be 4 instead of 2. Thus the name of the cycloaddition would be [4 + 4]-cycloaddition.
Diels-Alder Reaction
Next, we will discuss perhaps the most famous cycloaddition reaction. It happens to be a [4 + 2]-cycloaddition. Knowing these two bits of information, we should be able to piece together what reaction we are talking about: of course, it is the Diels-Alder reaction (Fig. 4)!
Fig. 4: Scheme of the Diels-Alder reaction.
In this reaction, an alkene adds to a conjugated diene; in this case, unlike the cases above, only 1,4-addition is permitted. The resulting product, then, is always the six-membered cyclohexene ring. For the purposes of this chapter, addition to multiple bonds, we describe the reactants as a conjugated diene and an alkene; however, in reality, the correct nomenclature is dienophile, instead of the alkene. This is a generalization of alkenes, although in undergraduate chemistry only Diels-Alder reactions with alkenes are discussed.
Ordinary alkenes do not react well in the Diels-Alder reaction, because for such alkenes the activation energy of the reaction is high. Electron-withdrawing groups are present on the alkene in many cases so as to increase its reactivity to the diene.
Because of the generalization to a dienophile, the close cousin of alkenes, alkynes, are also able to participate in the Diels-Alder reaction, which results in the formation of cyclohexadiene instead. Earlier we mentioned that a proof of the existence of benzynes (or arynes) was achieved by noting that a Diels-Alder reaction could take place between the aryne and a conjugated diene. The reaction is interesting because ordinary benzene itself cannot react via the Diels-Alder reaction unless drastic reaction conditions are used.
The activation of the dienophile is performed by the addition of electron-withdrawing groups to it; since the Diels-Alder reaction is simply an interaction of different charges, is it possible that the activation of the diene could also be achieved if electron-donating groups instead are added to it. This sentiment is indeed correct.
However, it is more common and oftentimes more convenient for there to be an electron-withdrawing group at the alkene instead. An ideal electron-withdrawing group would have to be easy to add to the alkene and easy to remove after the reaction concludes. What are some candidates for such electron-withdrawing groups? Common electron-withdrawing groups come to mind, but it is usually specialized reagents that are used.
We give two examples, of phenyl vinyl sulfones as well as phenyl vinyl sulfoxides. In the former case reaction with sodium and mercury is able to remove it. Note that for conjugated dienes, no activation is needed. Crucially, however, the diene must be in the cisoid conformation and not the transoid conformation (this means that the both alkenes are cis to each other, Fig. 5).
Fig. 5: Example of the cisoid and transoid conformations.
Usually, the diene and the dienophile react to form a single product; this holds true except in two cases. The first case is when both the diene and dienophile are asymmetrical. This would result in isomers. Alternatively, it is possible for rearrangements to occur.
The second case considers the possibility of rearrangements which are not common. In our discussion of the stereochemistry of this reaction, we consider it as the addition of the dienophile to the diene. Thus, the stereochemistry of the reaction is syn, meaning that the stereochemistry of the substituents (cis-trans) on the alkene carbons are retained. For example, a cis group in the alkene will remain cis after the Diels-Alder reaction.
So, what is the mechanism for the Diels-Alder reaction? Although it is highly likely that the mechanism would be the concerted pericyclic mechanism that we will mention first, there are two other mechanism that can also be considered.
We should note that it is completely possible for two mechanisms to operate in tandem with one another. In the first Diels-Alder mechanism, it is a concerted one-step mechanism with a six-centered transition state (Fig. 6).
Fig. 6: More accepted Diels-Alder mechanism.
The second mechanism is similar, but the alkene only reacts with one end of the diene in the first step. We note that this means at the end of the first step, the π bonds will be broken, but some carbons will still not have formed bonds with each other.
This means that they will be left with one electron each. As such, a diradical (or biradical) is formed. In the second step, logically, the radicals react with one another through a termination step to form the final, stable compound. The third mechanism is a variation of this second mechanism, suggesting that point charges, instead of radicals, exist, so the intermediate would be a diion.
Woodward-Hoffmann Rules
Generally there are two ways to apply these rules to cycloaddition reactions. These are the frontier orbital method and the Mobius-Huckel method. Both rules make use of orbitals, which we have not gone through in detail on this blog. We will look at the ‘simpler’ way of applying only, which is the frontier orbital method.
The frontier orbital method suggests that concerted mechanisms are only allowed if overlap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital is such that positive and negative lobes do not interact (or overlap).
Because of this, if we consider [2 + 2]-cycloaddition (pericyclic mechanism of two alkenes) from this point of view, we note that overlap is present between the + and - lobes of the two orbitals. This is difficult to explain in terms of words, and a diagram from March’s Advanced Organic Chemistry explains it much better (Fig. 7).
Fig. 7: Orbital overlap in thermal [2 + 2]-cycloaddition.
However, it is indeed possible for there to be a [2 + 2]-cycloaddition if it is not concerted. For example, the thermal [2 + 2]-cycloaddition is disallowed by the Woodward-Hoffmann rules, and thus does not take place; why can the photochemical [2 + 2]-cycloaddition take place?
To understand this, we have to remember the fact that when exposed to light, electrons are excited, and this changes the orbitals themselves. In the case of a photochemical [2 + 2]-cycloaddition, it is sufficiently changed that orbital overlap no longer causes overlap between opposite lobes, and thus this reaction would be permitted.
Finally, for the Diels-Alder reaction, if we look at diagrams of the orbitals, we can see that overlap is always permitted, no matter whether the alkene and conjugated diene are excited by photochemical methods or not.
References: Smith, M. (2013). March's Advanced Organic Chemistry. Wiley-Blackwell.