Steric effects on the catalytic activities of zinc(ii) complexes containing [12]aneN3 ligating units in the cleavage of the RNA and DNA model phosphates

Abstract

A series of N-methylated mono- and di-[12]aneN₃ ligands (5–9) have been synthesized and characterized. The steric effects on the catalytic activities of their mononuclear and dinuclear zinc(II) complexes in the cleavage of a RNA model 2-hydroxypropyl 4-nitrophenyl phosphate (HPNPP, 3) and a DNA model methyl 4-nitrophenyl phosphates (MPNPP, 4) in methanol have been investigated at 25 °C. In the cleavage of phosphate 3 catalyzed by the mononuclear complexes, derived from the N-methylation in the [12]aneN₃ backbone, the plots of k_obsversus [Zn(II)] changed from an upward curvature to linearity with increasing level of methylation, indicating that N-methylations led to a reduction of dinuclear association that was responsible for the synergetic effect. Compared to the activities of the complex with non-methylated di-[12]aneN₃ ligand, those of the dinuclear zinc(II) complex (Zn₂-8), which has the two N-methyl groups, were reduced by two orders of magnitude as measured by the second-order rate constants and synergetic effect in the cleavage of both model compounds. For reactions catalyzed by the fully N-methylated dinuclear complex (Zn₂-9), no synergetic effect was observed. Nevertheless, complex Zn₂-8 still showed the remarkable catalytic efficiency, with rate accelerations of 10^9–10-fold in the cleavage of each of the two phosphates relative to the background reactions, and the synergetic effects of up to 561 folds. pH jump experiments confirmed that the rate-limiting step in the cleavage of 3 by Zn₂-8 involved the binding process, while that in the reaction with 4 was the chemical cleavage of the P–O bond. Steric effects in the cleavage reactions were analyzed in detail and were compared with the electronic effect caused by oxy anion bridging group in the di-[12]aneN₃ ligand and also with the hydrophobic effect observed in other systems. The work has further confirmed that the combination of the cooperativity between two metal ions and a medium effect could result in excellent catalytic activities for the cleavage of phosphate diesters.