Rapid Three-Step Cleavage of RNA and DNA Model Systems Promoted by a Dinuclear Cu(II) Complex in Methanol. Energetic Origins of the Catalytic Efficacy

A dinuclear Cu(II) complex of 1,3-bis-N1-(1,5,9-triazacyclododecyl)propane with an associated methoxide (2-Cu(II)2:(-OCH3)) was prepared, and its kinetics of reaction with an RNA model (2-hydroxypropyl-p-nitrophenyl phosphate (1, HPNPP)) and two DNA models (methyl p-nitrophenyl phosphate (3) and iso-butyl p-chlorophenyl phosphate (4)) were studied in methanol solution at pH 7.2 ± 0.2. X-ray diffraction structures of 2-Cu(II)2:(-OH)(H2O)(CF3SO3-)3:0.5CH3CH2OCH2CH3 and 2-Cu(II)2:(-OH)((C6H5CH2O)2PO2-)(CF3SO3-)2 show the mode of coordination of the bridging -OH and H2O between the two Cu(II) ions in the first complex and bridging -OH and phosphate groups in the second. The kinetic studies with 1 and 3 reveal some common preliminary steps prior to the chemical one of the catalyzed formation of p-nitrophenol. With 3, and also with the far less reactive substrate (4), two relatively fast events are cleanly observed via stopped-flow kinetics. The first of these is interpreted as a binding step which is linearly dependent on [catalyst] while the second is a unimolecular step independent of [catalyst] proposed to be a rearrangement that forms a doubly Cu(II)-coordinated phosphate. The catalysis of the cleavage of 1 and 3 is very strong, the first-order rate constants for formation of p-nitrophenol from the complex being ∼0.7 s-1 and 2.4 × 10-3 s-1, respectively. With substrate 3, 2-Cu(II)2:(-OCH3) exhibits Michaelis−Mentin kinetics with a kcat/KM value of 30 M-1 s-1 which is 3.8 × 107-fold greater than the methoxide promoted reaction of 3 (7.9 × 10-7 M-1 s-1). A free energy calculation indicates that the binding of 2-Cu(II)2:(-OCH3) to the transition states for 1 and 3 cleavage stabilizes them by −21 and −24 kcal/mol, respectively, relative to that of the methoxide promoted reactions. The results are compared with a literature example where the cleavage of 1 in water is promoted by a dinuclear Zn(II) catalyst, and the energetic origins of the exalted catalysis of the 2-Cu(II)2 and 2-Zn(II)2 methanol systems are discussed.