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-<i>bis</i>-N<sub>1</sub>-(1,5,9-triazacyclododecyl)propane with an associated methoxide (<b>2</b>-Cu(II)<sub>2</sub>:(<sup>-</sup>OCH<sub>3</sub>)) was prepared, and its kinetics of reaction with an RNA model (2-hydroxypropyl-<i>p</i>-nitrophenyl phosphate (<b>1</b>, HPNPP)) and two DNA models (methyl <i>p</i>-nitrophenyl phosphate (<b>3</b>) and <i>iso</i>-butyl <i>p</i>-chlorophenyl phosphate (<b>4</b>)) were studied in methanol solution at pH 7.2 ± 0.2. X-ray diffraction structures of <b>2</b>-Cu(II)<sub>2</sub>:(<sup>-</sup>OH)(H<sub>2</sub>O)(CF<sub>3</sub>SO<sub>3</sub><sup>-</sup>)<sub>3</sub>:0.5CH<sub>3</sub>CH<sub>2</sub>OCH<sub>2</sub>CH<sub>3</sub> and <b>2</b>-Cu(II)<sub>2</sub>:(<sup>-</sup>OH)((C<sub>6</sub>H<sub>5</sub>CH<sub>2</sub>O)<sub>2</sub>PO<sub>2</sub><sup>-</sup>)(CF<sub>3</sub>SO<sub>3</sub><sup>-</sup>)<sub>2</sub> show the mode of coordination of the bridging <sup>-</sup>OH and H<sub>2</sub>O between the two Cu(II) ions in the first complex and bridging <sup>-</sup>OH and phosphate groups in the second. The kinetic studies with <b>1</b> and <b>3</b> reveal some common preliminary steps prior to the chemical one of the catalyzed formation of <i>p</i>-nitrophenol. With <b>3</b>, and also with the far less reactive substrate (<b>4</b>), 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 <b>1</b> and <b>3</b> is very strong, the first-order rate constants for formation of <i>p</i>-nitrophenol from the complex being ∼0.7 s<sup>-1</sup> and 2.4 × 10<sup>-3</sup> s<sup>-1</sup>, respectively. With substrate <b>3</b>, <b>2</b>-Cu(II)<sub>2</sub>:(<sup>-</sup>OCH<sub>3</sub>) exhibits Michaelis−Mentin kinetics with a <i>k</i><sub>cat</sub>/<i>K</i><sub>M</sub> value of 30 M<sup>-1</sup> s<sup>-1</sup> which is 3.8 × 10<sup>7</sup>-fold greater than the methoxide promoted reaction of <b>3</b> (7.9 × 10<sup>-7</sup> M<sup>-1</sup> s<sup>-1</sup>). A free energy calculation indicates that the binding of <b>2</b>-Cu(II)<sub>2</sub>:(<sup>-</sup>OCH<sub>3</sub>) to the transition states for <b>1</b> and <b>3</b> 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 <b>1</b> in water is promoted by a dinuclear Zn(II) catalyst, and the energetic origins of the exalted catalysis of the <b>2</b>-Cu(II)<sub>2</sub> and <b>2</b>-Zn(II)<sub>2</sub> methanol systems are discussed.