A model for catalytically active zinc(II) ion in liver alcohol dehydrogenase: A novel "hydride transfer" reaction catalyzed by zinc(II)-macrocyclic polyamine complexes

Article abstract of DOI:10.1021/ja00052a007

The role of Zn^II ion at the active center of liver alcohol dehydrogenase has been well-defined for the first time by the comparative studies of Zn^II[12]aneN₃, 1 ([12]aneN₃ = 1,5,9-triazacyclododecane, L₁), Zn^II[12]aneN₄, 2 ([12]aneN₄ = 1,4,7,10-tetraazacyclododecane, L₂), Zn^II[14]aneN₄, 3 ([14]aneN₄ = 1,4,8,11-tetraazacyclotetradecane, L₃), and free Zn^II salts, 4. Variations in Zn^II acidity and coordination environment in these complexes result in varying degrees of catalytic activity in the reduction of p-nitrobenzaldehyde (9) and an NAD⁺ model compound (18) with alcohols as the "hydride" sources (e.g., 2-PrOH) to p-nitrobenzyl alcohol (10) and the corresponding NADH model compounds (19 and 20), respectively. Among Zn^II species tested, the Zn^II complex of macrocyclic triamine [12]aneN₃, 5 (L₁Zn^II-OH)₃·(TfO) ₃·TfOH (TfO = CF₃SO₃^-), was by far the most effective catalyst: 10 was obtained from 9 in 7820% yield (based on the concentration of Zn^II) in the presence of 5 (0.8 mol %) in refluxing 2-PrOH for 24 h. The Zn^II complex 5, also promotes the "hydride transfer" from 2-PrOH to an NAD⁺ model compound, N-benzylnicotinamide chloride (18), to yield the 1,4-adduct, N-benzyl-1,4-dihydronicotinamide (19), almost exclusively. It is concluded, from the comparison of 5 with other Zn^II complexes of [12]aneN₄ and [14]aneN₄, that the most acidic and coordinatively least saturated Zn^II in L₁ catalytically generates zinc(II)-alkoxide complex to facilitate the hydride transfer to the hydride acceptor on the Zn^II coordination sphere. The present study provides the first chemical model illustrating the significance of the Zn^II acidity and the steric requirement around Zn^II coordination sphere in the hydride transfer reaction (from alcohol) catalyzed by Zn^II-containing alcohol dehydrogenases (ADH).