The interaction of zinc(II) and hydroxamic acids and a metal-triggered lossen rearrangement

Abstract

The structure and reactivity of a complex of zinc(II), water, acetic acid, and acetohydroxamic acid, in which one of the acids is deprotonated, is investigated by means of mass spectrometry, labeling studies, and density functional calculations to unravel the exceptional binding properties of hydroxamic acids towards zinc-containing enzymes at the molecular level. It is shown that acetohydroxamic acid is deprotonated in the complex, whereas acetic acid is present in its neutral form. The binding energies of the Iigands towards zinc increase in the following order: water < acetic acid < acetohydroxamic acid. The structure of the complex and its fragmentation provide experimental evidence for the proposed mode of operation of drugs based on hydroxamic acids. Furthermore, coordinatively unsaturated complexes of zinc and acetohydroxamic acid undergo a zinc-assisted Lossen rearrangement followed by elimination of water if acetohydroxamic acid is present as a neutral ligand, or by loss of methylisocyanate if acetohydroxamic acid is deprotonated. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.