Fluorine substitution enhances the reactivity of substituted phenyl radicals toward organic hydrogen atom donors

Phenyl radicals with different positively charged, chemically inert substituents in the para position were generated by collision-activated dissociation of para-substituted iodobenzene ions in the gas phase inside a Fourier-transform ion cyclotron resonance mass spectrometer. The reactivity of the radicals was examined toward organic hydrogen atom donors. The findings parallel those made by others for neutral radicals in solution. For example, the efficiency of hydrogen atom abstraction increases in the expected order phenol < thiophenol < benzeneselenol. Inspite of great exothermicity, hydrogen atom abstraction by the charged phenyl radicals occurs at a small fraction of the gas-phase collision rate, suggesting the presence of a significant barrier on the reaction coordinate. Fluorine substitution on the phenyl ring was found to drastically enhance the reaction rate for all the substrates studied. For example, hydrogen abstraction from thiophenol by the (2,3,5,6-tetrafluoro-4-dehydrophenyl)trim ion occurs at 21% of the collision rate while the (4-dehydrophenyl)trimethylphosphonium ion reacts by hydrogen atom abstraction at less than 0.3% of the collision rate. In order to probe whether a similar rate enhancement is expected for hydrogen atom abstraction from a sugar unit in DNA, a key step in the action of many antitumor drugs, tetrahydrofuran was examined as a simple model of the sugar moiety. This substrate was found to demonstrate even greater sensitivity toward fluorine substitution in the phenyl radical than the other hydrogen atom donors studied. Hence, fluorine substitution is likely to drastically increase the activity of those antitumor drugs whose action is based on DNA cleavage by polyatomic organic radicals.