Bergman cyclization

The Bergman cyclization or Bergman reaction or Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor ("Scheme 1") ["p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure" Richard R. Jones, Robert G. Bergman J. Am. Chem. Soc.; 1972; 94(2); 660-661. [http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1972/94/i02/f-pdf/f_ja00757a071.pdf Abstract] ] . It is named for the American chemist Robert George Bergman (b. 1942). The reaction product is a derivative of benzene.

The reaction proceeds by a thermal reaction or pyrolysis (above 200°C) forming a short-lived and very reactive para-benzyne biradical species. It will react with any hydrogen donor such as 1,4-cyclohexadiene which converts to benzene. When quenched by tetrachloromethane the reaction product is a 1,4-dichlorobenzene and with methanol the reaction product is benzyl alcohol.

When the enyne moiety is incorporated into a 10-membered hydrocarbon ring (e.g. cyclodeca-3-ene-1,5-diyne in "scheme 2") the reaction, taking advantage of increased ring strain in the reactant, is possible at the much lower temperature of 37°C.

Naturally occurring compounds exist containing the same 10-membered enyne ring and are found to be cytotoxic. These compounds generate the diradical intermediate described above which cause single- and double stranded DNA cuts. Novel drug research attempts to make use of this property, mylotarg one of them ["Design and synthesis of heterocycle fused enediyne prodrugs activable at will"Luca Banfi, Andrea Basso, Giuseppe Guanti, and Renata Riva Arkivoc 2006 HL-1786GR 261-275 [http://www.arkat-usa.org/ark/journal/2006/I07_ICHC-20/1786/HL-1786GR%20as%20published%20mainmanuscript.pdf Abstract] ] .

A biradical mechanism is also proposed for the formation of certain biomolecules found in marine "sporolides" that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt provides the halogen. A model reaction with the enediyene "cyclodeca-1,5-diyn-3-ene", lithium bromide as halogen source and acetic acid as hydrogen source in DMSO at 37°C supports the theory [Nucleophilic Addition to a p-Benzyne Derived from an Enediyne: A New Mechanism for Halide Incorporation into Biomolecules Charles L. Perrin, Betsy L. Rodgers, and Joseph M. O'Connor J. Am. Chem. Soc.; 2007; ASAP Web Release Date: 23-Mar-2007; (Article) DOI|10.1021/ja070023e] ["New Route For Halide Addition" Stu Borman Chemical & Engineering News April 2 2007 [http://pubs.acs.org/cen/news/85/i15/8515news1.html Link] ] :

The reaction is found to be first order in enediyne with the formation of p-benzyne A as the rate-limiting step. The halide ion then donates its two electrons in the formation of a new Br-C bond and radical electron involved is believed to shuttle over a transient C1-C4 bond forming the anion intermediate B. The anion is a powerful base, stripping protons even from DMSO to final product. The dichloride or dihydrogen product (tetralin) never form.

External links

* "Bergman Cycloaromatization" [http://www.chem.wisc.edu/areas/organic/studsemin/erwin/bergman_files/frame.htm Powerpoint] Whitney M. Erwin 2002

References