A minimalist approach to understanding the efficiency of mononuclear Zn(ii) complexes as catalysts of cleavage of an RNA analog

Abstract

Mononuclear complexes between Zn²⁺ and the following four macrocycles were prepared: 1,4,7,10-tetraazacyclododecane (1), 1-oxa-4,7,10-triazacyclododecane (2), 1,5,9-triazacyclododecane (3) and 1-hydroxyethyl-1,4,7-triazacyclononane (4). The pH rate profiles of values of the observed second-order rate constant log (k_Zn)_app for Zn(X)(OH₂)-catalyzed cleavage (X = 1, 2, 3 and 4) of 2-hydroxypropyl-4-nitrophenyl phosphate (HpPNP) show downward breaks centered at the pK_a for ionization of the respective zinc bound water. At low pH, where the rate acceleration for the catalyzed reaction is largest, the stabilizing interaction between the catalyst and the bound transition state is 5.7, 7.4, 7.4 and 5.9 kcal mol⁻¹ for the reactions catalyzed by Zn(1)(OH₂), Zn(2)(OH₂), Zn(3)(OH₂) and Zn(4)(OH₂), respectively. The interactions between the metal cation and the macrocycle cause either a modest increase or reduction in transition state stabilization compared with 6.6 kcal mol⁻¹ stabilization for catalysis by Zn(OH₂)₆. The best Zn(II)–macrocycle catalysts are those for which the interactions between the metal ion and macrocycle are the weakest. Inhibition studies show that each of the four catalysts form complexes with phosphate and oxalate dianions with a much higher affinity than diethyl phosphate monoanion, consistent with stronger interaction of the catalysts with the transition state dianion compared with the substrate monoanion HpPNP. The pH-dependence of methyl phosphate inhibition of Zn(2) catalyzed cleavage of HpPNP shows that only the Zn(2)(OH₂) species binds the inhibitor. This result is consistent with a mechanism that has Zn(2)(OH₂) as the active catalytic species.