Multiple modes of activation in phosphate diester hydrolysis

A dinuclear copper(II) complex has been investigated for promoting the transesterification of a phosphate diester, 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP), that is a model for RNA. Rate enhancements of over 10$ sp5$ have been obtained at neutral pH over the background hydroxide rate. For this study the dinucleating ligand 2,6-bis ((bis(benzimidazolymethyl)amino)methyl) -p-cresol was prepared and the reactivity of the copper(II) complex for cleaving 2-hydroxypropyl-4-nitrophenyl phosphate was determined. The two metals were shown to be acting cooperatively by comparing the reactivity of the dinuclear complex to that of a mononuclear complex, copper(II) 2-(bi(benzimidazolymethyl)amino)methyl-4,6-dimethylphenol. A mechanism involving double Lewis acid activation of HPNP is proposed to account for the 10$ sp5$ rate acceleration.The reactivity of mononuclear Cu(II) and Zn(II) complexes of 2,9-diamino-1,10-phenanthroline (DAP) have been investigated for promoting the hydrolysis of phosphate diesters with good and poor leaving groups. The CuDAP and ZnDAP complexes were shown to be able to provide 10$ sp{10}$ and 10$ sp7$ orders of magnitude rate acceleration for hydrolyzing $2 sp prime,3 sp prime$-cAMP. A novel mechanism which combines metal ion catalysis with intramolecular hydrogen bonding has been proposed to account for the unprecedented rate acceleration. Crystallographic evidence and potentiometic titration data are provided, in addition to kinetic data, to support the proposed mechanism. The results with CuDAP are compared with the copper(II) complex of 2,9-dimethyl-1,10-phenanthroline (CuNeo) to evaluate the rate enhancement provided by intramolecular hydrogen bonding. It is found that intramolecular hydrogen bonding interactions increase the reactivity of CuDAP relative to CuNeo by a factor of 10$ sp3.