Synthesis and coordination chemistry of tripodal thioether-pyrazole ligands and their application to modeling reactivity of zinc thiolate enzymes

Three new borate ligands, [PhB(CH2SCH3)2(pz)] -, [PhB(CH2SBut) 2(pz)]- and [PhB(CH2SBu t)2(pzt Bu)]- (pz = pyrazole, pzt Bu = 3-tert-butyl pyrazole) have been prepared to provide a new class of mixed donor [S2N] ligands for coordination chemistry. Reactions of [PhB(CH2SCH3)2(pz)]- with NiII, CoII and FeII yield 2:1 octahedral metal complexes. The [PhB(CH2SBu t)2(pz)] ligand with the bulkier substitutent on sulfur ions provides lower coordinate complexes, while reactions with NiCl 2 and Ni(acac)2 (acac = acetylacetonate) produced the chloride bridged dimer, {lcub}[PhB(CH2SBut) 2(pz)/NiCl{rcub}2 and the five coordinate square pyramidal complex, [PhB(CH2SBut)2(pz)]Ni(acac). Contrasting the straightforward behavior of nickel salts, the CoII coordination chemistry was more complex with outcomes sensitive to the reaction medium. Upon dissolution in different solvent, the reactions gave either a chloride-bridged dimer, {lcub}PhB(CH2SBu t)2(pz)CoCl{rcub}2, or a 2:1 tetrahedral complex, [PhB(CH2SBut)2-(pz)] 2Co in which the borate ligand coordinates in a kappa2 mode.; A series of mononuclear zinc thiolate complexes have been prepared and fully characterized. The reactions of the complexes with alkyl halides leading to zinc halides and the corresponding thioethers have been examined by kinetic methods. In toluene, all reactions obey a second-order rate law with activation parameters consistent with a SN2 attack of the zinc-bound thiolate on the carbon electrophile. Intramolecular hydrogen-bonding of an amide N-H to the thiolate sulfur reduces the thiolate nucleophilicity and consequently, the rates of alkylation more than thirty-fold at 25°C. Hydrogen bonding shows an inverse isotope effect, kH/kD = 0.33 (60°C) ascribed to differential H-bonding for the two isotopomers due to zero point energy differences. These model studies provide the first quantitative evaluation of hydrogen bonding on reaction rates relevant to zinc thiol-activating proteins.