Diels–Alder Reaction

Introduction

How does a chemical reaction proceed? This is one of the most important questions in chemistry and still drives research today. Traditionally, reactions have been classed as either ionic or radical processes. But there is a third class: a pericyclic reaction. The pericyclics, named because of their concerted curly arrow mechanisms, are a class of reaction governed by orbital symmetry. Often triggered by heat or light, they are some of the ‘greenest’ reactions, frequently achieving 100% atom economy.

Perhaps the most famous pericyclic reaction is the Diels–Alder cycloaddition. Awarded a Nobel Prize in 1950, this reaction has been used extensively in both industry and academia. This article will explore how the Diels–Alder reaction works, supported by examples of its use in total natural product syntheses.

Diels-Alder reaction: orbital considerations

The Diels–Alder reaction proceeds thermally, with a diene and a dienophile interacting with the correct orbital phases. To explain this, let’s consider the reaction of butadiene (diene) with ethene (dienophile) to form cyclohexene.

In butadiene, there are four valence p orbitals, each of which can interact in phase (same colours touching) or out of phase (different colours overlapping), leading to the generation of four molecular orbitals. For ethene, two molecular orbitals are generated, as there are only two valence p orbitals.

For all chemical reactions to proceed, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the reactants must overlap in phase. Considering the phases of the diene HOMO and the dienophile LUMO shows they can interact favourably. The curly arrows move cyclically to generate cyclohexene.

Stereochemistry

In terms of stereochemistry, the Diels–Alder reaction follows two rules which govern its reactivity. Firstly, the diene starting material must be s‑cis, meaning the double bonds must be cis to one another for the orbital overlap to be successful. Secondly, the Diels–Alder reaction always maintains any stereochemical information of the starting material. For example, reacting butadiene with dimethyl maleate always gives a cis product. Both isomers of the product will form, as this reaction is not stereoselective.

Applications of the Diels–Alder Reaction

The Diels–Alder reaction has a rich and diverse history in the synthesis of total natural products. In 1952, Woodward et al. were the first to incorporate a Diels–Alder reaction into a total synthesis of cholesterol. Woodward also used a Diels–Alder reaction in his famous synthesis of reserpine, a medicinal product used to treat high blood pressure.

Another interesting example of the Diels–Alder reaction in a complex synthesis was Danishefsky’s synthesis of myrocin C, an antibiotic with anti‑tumour properties. The ingenuity of this synthesis is that the intermediary fragment was specifically designed to undergo an intramolecular Diels–Alder reaction.

Conclusion

In conclusion, the Diels–Alder reaction is a titan of synthetic chemistry. As the chemical industry continues to adopt more sustainable chemistry, the Diels–Alder reaction is still as relevant as it was almost 100 years ago. While this article has centred on the Diels–Alder reaction, the pericyclic reactions are far more extensive. There are further cycloadditions as well as electrocyclisations, sigmatropic rearrangements and group transfer reactions. These transformations show the elegance of synthetic chemistry and re‑emphasise the importance of symmetry in all chemical disciplines.

Written by Antony Lee

Related article: Symmetry in chemistry