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 k_cat/K_M 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.