Bergman cyclization of enediynes to produce 1,4-benzenoid diradicals has been attributed to the potent ability of natural products like calicheamicin and dynemicin to cleave DNA. Formally, Bergman cyclization is a two-step process consisting of cyclization to a diradical followed by hydrogen-atom abstraction from a donor molecule like 1,4-cyclohexadiene. While cyclization of the parent enediyne, (<i>Z</i>)-hex-3-ene-1,5-diyne, is rate-determining it is well established that upon benzannelation cyclization of 1,2-diethynylbenzene is reversible and the overall rate of enediyne disappearance becomes dependent on the concentration of 1,4-cyclohexadiene. To explore the effect of extended benzannelation orientation on enediyne cyclization, enthalpy barriers and reaction enthalpies were calculated for the quinoxalenediyne isomers 5,6-diethynylquinoxaline and 6,7-diethynylquinoxaline. Calculations indicate angular benzannelation results in decreased cyclization endothermicity compared to the linear derivative that may render Bergman cyclization irreversible. To study this effect experimentally we have synthesized these quinoxalenediyne isomers to examine reaction kinetics as a function of 1,4-cyclohexadiene concentration. Initial kinetic data monitoring the rate of enediyne disappearance for the linear derivative, 6,7-diethynylquinoxaline, show a strong dependence on 1,4-cyclohexadiene concentration. In comparison, the angular isomer, 5,6-diethynylquinoxaline, demonstrates a faster rate of cyclization that is less sensitive to 1,4-cyclohexadiene concentration. The syntheses of our quinoxalenediyne models and ongoing kinetic studies will be presented.

Syntheses and kinetic studies on the Bergman cyclization of diethynylquinoxaline isomers

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.