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 (L1-Zn(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).
