Thiolate exchange in [Tm^R]ZnSR′ complexes and relevance to the mechanisms of thiolate alkylation reactions involving zinc enzymes and proteins

The zinc and cadmium thiolate complexes [ Tm^{Bu t} ] MSCH₂ C ( O ) N ( H ) Ph (M = Zn, Cd) may be obtained via treatment of the respective methyl complex [ Tm^{Bu t} ] MMe with PhN(H)C(O)CH₂SH. The molecular structure of [ Tm^{Bu t} ] ZnSCH₂ C ( O ) N ( H ) Ph has been determined by X-ray diffraction, thereby demonstrating the presence of an intramolecular N-H ⋯ S hydrogen bond between the amide N-H group and thiolate sulfur atom. [ Tm^But ] ZnSCH₂ C ( O ) N ( H ) Ph mimics the function of the Ada DNA repair protein by undergoing alkylation with MeI to give [ Tm^{Bu t} ] ZnI and MeSCH₂C(O)N(H)Ph. A series of crossover experiments and ¹H NMR magnetization transfer studies establish that thiolate exchange between [Tm^R]ZnSR′ derivatives is facile in this system, an observation that supports the previous suggestion that the alkylation of [Tm^Ph]ZnSCH₂C(O)N(H)Ph by MeI may proceed via a sequence that involves dissociation of [PhN(H)C(O)CH₂S]^-.