Bergman cyclization

What is Bergman cyclization?

The Bergman cyclization is a reaction that forms aromatic compounds from (Z)-enediynes through a 1,4-biradical intermediate. Although this reaction was discovered in the 1940s and 1950s, it was not fully understood until 1972 when Bergman proposed and proved the existence of the 1,4-aryldiradical intermediate in the gas phase.

Bergman cyclization - general reaction scheme
Bergman cyclization

The Bergman cyclization gained attention in the 1980s with the discovery of enediyne antibiotics such as calicheamicin, esperamicin, dynemicin, and kedarcidin, which are potent antibiotic antitumor agents that rely on the Bergman cyclization to cleave DNA. The Bergman cyclization is an endothermic reaction, and the formed 1,4-biradical is a reactive σ,σ-biradical that can abstract hydrogen atoms from the backbone of DNA. The reaction can be affected by various factors such as solvent, molecular strain energy, distance between the acetylenic termini, and electronic effect. The Bergman cyclization can be carried out either thermally or photochemically, and the formed 1,4-biradical intermediate can either polymerize or initiate a radical polymerization process. When a heteroatom replaces the carbon-carbon double bond, the corresponding cyclization is called aza-Bergman cyclization. This cyclization has been used to prepare macrocyclic compounds and is also important in photodynamic therapy and biomedicine.

References

p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure
Richard R. Jones and Robert G. Bergman
Journal of the American Chemical Society 1972 94 (2), 660-661
DOI: 10.1021/ja00757a071

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