EPR Spectroscopic Reinvestigation of the Activation of Iron Complexes of PMAH as a Bleomycin Model

The structure and reactivity of iron complexes of PMAH, which contains ligands that mimic the metal binding domain of iron bleomycin (FeBLM), have been studied using EPR spectroscopy. It had been reported [Guajardo, R. J.; Hudson, S. E.; Brown, S. J.; Mascharak, P. K. J. Am. Chem. Soc. 1993, 115, 7971] that iron complexes of PMAH can be activated to a ferric hydroperoxide, a structural analog by activated BLM, by various routes, including reaction of [FeIIIPMA]2+ with iodosylbenzene (PhIO), methanol, and base. We show that with or without PhIO, the latter reaction produces the methoxide complex of FeIIIPMA, and not the hydroperoxide, contrary to the previous report. Thus, O−O bond formation through generation of a ferric hydroperoxide does not occur. The same methoxide complex (g = 2.28, 2.18, 1.93) is generated by the addition of organic base and CH3OH, or LiOCH3, to [FeIIIPMA]2+. The formation of this [CH3O−FeIIIPMA]+ complex is confirmed by EPR titration of [FeIIIPMA]2+ with -OCH3 and by electrospray mass spectrometry. In contrast, the hydroperoxy complex of FeIIIPMA (g = 2.22, 2.17, 1.94) can be generated by the reaction of [FeIIIPMA]2+ with hydrogen peroxide or during aerobic oxidation of [FeIIPMA]+. The present results illustrate that activation of iron complexes of PMAH occur under conditions that produce activated BLM and further demonstrate that reaction of [FeIIIPMA]2+ with PhIO and base does not provide a route to either a hypervalent iron species or a hydroperoxide intermediate. These results agree with the finding that PhIO cannot be used to generate activated bleomycin [Sam, J. W.; Tang, X.-J.; Magliozzo, R. S.; Peisach, J. J. Am. Chem. Soc. 1995, 117, 1012].