The cyclization of the RNA model 2-hydroxypropyl p-nitrophenyl phosphate (HPNPP, 1) promoted by Zn2+ alone and the 1,5,9-triazacyclododecane complex of Zn2+ (Zn2+:[12] aneN(3)) is studied in ethanol in the presence of 0.5 equiv of -OEt/Zn2+ to investigate the effect of a low polarity/dielectric medium on a metal-catalyzed reaction of biological relevance. Ethanol exerts a medium effect that promotes strong binding of HPNPP to Zn2+, followed by a dimerization to form a catalytically active complex (HPNPP: Zn2+)(2) in which the phosphate undergoes cyclization with a rate constant of k(cat) = 2.9 s(-1) at (s)(s)pH 7.1. In the presence of the triaza ligand: Zn2+ complex, the change from water to methanol and then to ethanol brings about a mechanism where two molecules of the complex, suggested as EtOH: Zn2+:[12] aneN(3) and its basic form, EtO -: Zn2+:[12] aneN(3), bind to HPNPP and catalyze its decomposition with a rate constant of k(cat) of 0.13 s(-1) at (s)(s)pH 7.1. Overall, the acceleration exhibited in these two situations is 4 x 10(14)-fold and 1.7 x 10(12)-fold relative to the background ethoxide-promoted reactions at the respective (s)(s)pH values. The implications of these findings are discussed within the context of the idea that enzymatic catalysis is enhanced by a reduced effective dielectric constant within the active site.