What Is Bergman Cyclization?
Definition
The Bergman cyclization, first reported by Robert R. Bergman in 1972, is a thermally or photochemically induced reaction that converts enediynes (1,5-diyne systems) into aromatic para-benzyne diradical intermediates, which subsequently undergo hydrogen abstraction or trapping to form substituted aromatic compounds. This reaction has garnered significant attention due to its pivotal role in the biosynthesis and activity of enediyne antitumor antibiotics, as well as its synthetic utility in constructing complex polycyclic frameworks.
History
In 1972, Bergman reported that cis-1,5-diyne-3-ene can undergo thermal rearrangement to produce highly reactive 1,4-diradical benzene. Although such reactions have been reported before, Bergman was the first to use diradical intermediates to explain his observed experimental results. The unique properties of the Bergman reaction have attracted the attention of physical organic chemistry and theoretical chemistry, and its mechanism has been further studied. The discovery of enediyne natural products such as neocarzinostatin, calicheamincin, esperamicin, dynemicin A, etc. in 1985 and the study of their biological activities have made this field widely concerned. These natural products of enediynes with highly strained structures can be activated at room temperature and trigger the Bergman reaction, generating highly reactive diradicals, damaging genes, and showing extremely high cytotoxicity.
- Reagents: Typically heat or light (no added reagents); solvents (e.g., benzene, toluene) may act as inert media.
- Reactants: Enediynes (Conjugated 1,5-diyne-3-ene systems, e.g., (Z)-hexa-3-ene-1,5-diyne).
- Products: Stabilized aromatic compounds (e.g., naphthalene derivatives) after hydrogen abstraction or trapping.
- Reaction type: Cyclization reaction (carbocyclic).
- Related reactions: Myers-Saito cyclization, Schmittel cyclization, Diels-Alder reaction.
Fig 1. Bergman cyclization reaction and its mechanism. [1]
Mechanism of Bergman Cyclization
Driven by the research on enediynes as natural antibiotics, organic chemists have tried to synthesize a variety of conjugated unsaturated molecules that can aromatize and generate diradicals. There have been many studies and summaries on the Bergman thermal rearrangement reaction. Many experiments support the existence of diradical intermediates, and the reaction activity is affected by many factors such as molecular geometry, substituent electronic effects, volume effects, and free radical quencher concentration. In general, the Bergman cyclization proceeds via a concerted or stepwise mechanism depending on substituents and reaction conditions:
- Initiation: Thermal activation (~200°C) or photoexcitation induces cyclization of the enediyne into a strained cyclic allene intermediate.
- Diradical Formation: The cyclic allene undergoes bond reorganization to generate a reactive para-benzyne diradical species.
- Termination: The diradical abstracts hydrogen atoms from the solvent or surrounding medium (e.g., H-donors like 1,4-cyclohexadiene) to yield substituted benzene derivatives. Alternatively, the diradical can be trapped by nucleophiles or participate in cascade cyclizations.
Key Factors Influencing Reactivity
- Strain Relief: Enediynes with conjugated substituents (e.g., electron-withdrawing groups) lower the activation energy by stabilizing transition states.
- Geometric Constraints: Proximity of the terminal alkynes (optimal spacing: ~3.2 Å) facilitates cyclization.
- Solvent Effects: High-boiling solvents (e.g., decalin, xylene) and inert atmospheres minimize side reactions.
Application Examples of Bergman Cyclization
- Example 1: The work of Eshani Das et al. reported excellent regioselectivity (>99%) for the generation of p-benzynes in high yields by Bergman cyclization of unsymmetrical 1,2-dialkynylbenzene in the form of a cyclic enediyne with retention of the ortho-alkoxy group. [2]
- Example 2: Unciaphenol (2) is an oxygenated analog of the Bergman cyclization product of uncialamycin (1). Unciaphenol exhibits anti-HIV activity in vitro against viral strains that are resistant to clinically used antiretroviral therapy. [3]
Fig 2. Synthetic examples via Bergman cyclization reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 35-37.
- Das, Eshani, et al. The Journal of Organic Chemistry, 2019, 84(5), 2911-2921.
- Williams, David E., et al. Organic letters, 2015, 17(21), 5304-5307.
