Cycloaddition Core Concepts
A cycloaddition is a type of reactions which combines different molecules or different parts of the same reaction to create a closed loop.
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Cycloaddition Nomenclature
Cycloadditions are reactions that form new loops within a molecule by taking pi bonds and creating new sigma bonds. Even though there are many types of such reactions, they are classifiable by the size the reactants and the products. Cycloaddition reactions are generally classified as a (X + Y) cycloaddition, where x refers to the number of existing sigma bonds in the reactants and y refers to the number of bonds created to complete the cycle. X+Y is the number of atoms in the new cycle.
Diels-Alder (4+2) Cycloaddition
Overview
The Diels-Alder cycloaddition is one of the most well-known and used cycloadditions. In summary, the Diels Alder forms a cyclohexene from a diene and an alkene. This 6 membered ring is ubiquitous in organic molecules. Given that these reactions occur very readily and in high yield, the Diels-Alder is very important. The resulting product has a left over double bond, which upon hydrogenation, creates cyclohexane derivatives. Famous for its versatility, the Diels-Alder allows virtually any alkene to react with most dienes, even on the same molecule.
Mechanism
This reaction occurs in polar organic solvents, such as water, acetone, or DMF with mild heating and a Lewis acid as a catalyst. To begin with, the pi bond from the alkene donates an electron pair to one of the carbons on the diene. Then, the other diene pi bond donates an electron pair to the other end of the alkene. This closes the loop, however, it is energetically more stable to have the remaining pi bond in the loop migrate one carbon towards the middle. We have a much more detailed article about the stereochemistry and mechanism here.
2+2 Photoaddition
The 2+2 cycloaddition is also very useful because it can create the strained cyclobutane ring which is difficult to synthesize with other methods. Sometimes known as the 2+2 photoaddition, this reaction requires UV light to mobilize the electrons because these photons have the perfect energy. The two alkenes must be close to each other for a comparatively long time, so these alkenes are usually part of the same molecule. UV light causes the pi bonds to temporarily weaken, then allowing the migration of this electron pair to a carbon on the opposite molecule. This happens another time in a symmetric manner to create the square shape of cyclobutane
3+2 Cycloaddition (1,3 Dipolar Cycloaddition)
The 3+2 cycloaddition is a useful reaction to create a 5-membered ring with some heteroatoms (usually N, O, and S). In this reaction, due to the uneven number of bonds, one of the reactants must have a resonance structure. Elements with a high electronegativity cause this resonance, such as oxygen. The charged structure is very reactive and can rearrange the pi bonds with an alkene to close the loop.
Click Chemistry
Click chemistry is a type of 1,3 Dipolar cycloaddition between an alkyne and an azide to create a triazole ring. This reaction started a field called green chemistry chiefly focusing on creating new synthetic methods without expensive and toxic solvents and catalyst. This reaction can take place in cells with a fluorescent reagent to preform various assays. It is so significant that it won the Nobel Prize in Chemistry in 2022.
Intramolecular Cycloadditions
Most cycloadditions involve the rearrangement of pi bonds between exclusively carbon-containing moieties, however, there are some special classes of reactions which, while not exclusively cycloaddition reactions, can undergo cycloadditions with itself. Such a reaction where a molecule creates a cycle by reacting with itself is an intramolecular cycloaddition.
Aldol Reactions
Aldol reactions can close rings when an alkene is present one carbon away from a carbonyl. This configuration of atoms is known as a conjugated carbonyl, and it can react with a carbon situated between two really electronegative groups to close the loop. We have a more detailed article about this reaction here.
Pinacol Couplings
Pinacol couplings are a rare type of reaction paramount to natural product chemistry to produce a ring with two alcohols next to each other. The reaction must contain two ketones separated by two or three carbons and requires a samarium based catalyst. One of the pi bonds is used to close the loop while the other is lost to the catalyst. The two alcohols are added to the same side (known as syn addition).
Cycloaddition Practice Problems
