DFT Computational Study of the Methanolytic Cleavage of DNA and RNA Phosphodiester Models Promoted by the Dinuclear Zn^(II) Complex of 1,3-Bis(1,5,9-triazacyclododec-1-yl)propane

A density functional theory study of the cleavage of a DNA model [<i>p</i>-nitrophenyl methyl phosphate (<b>2</b>)] and two RNA models [<i>p</i>-nitrophenyl 2-hydroxypropyl phosphate (<b>3</b>) and phenyl 2-hydroxypropyl phosphate (<b>4</b>)] promoted by the dinuclear Zn^(II) complex of 1,3-bis­(1,5,9-triazacyclododec-1-yl)­propane formulated with a bridging methoxide (<b>1a</b>) was undertaken to determine possible mechanisms for the transesterification processes that are consistent with experimental data. The initial substrate-bound state of <b>2</b>:<b>1a</b> or <b>3</b>:<b>1a</b> has the two phosphoryl oxygens bridging Zn^(II)₁ and Zn^(II)₂. For each of <b>2</b> and <b>3</b>, four possible mechanisms were investigated, three of which were consistent with the overall free energy for the catalytic cleavage step for each substrate. The computations revealed various roles for the metal ions in the three mechanisms. These encompass concerted or stepwise processes, where the two metal ions with associated alkoxy groups [Zn^(II)₁:(⁻OCH₃) and Zn^(II)₁:(⁻O-propyl)] play the role of a direct nucleophile (on <b>2</b> and <b>3</b>, respectively) or where Zn^(II)₁:(⁻OCH₃) can act as a general base to deprotonate an attacking solvent molecule in the case of <b>2</b> or the attacking 2-hydroxypropyl group in the case of <b>3</b>. The Zn^(II)₂ ion can serve as a spectator (after exerting a Lewis acid role in binding one of the phosphates’ oxygens) or play active additional roles in providing direct coordination of the departing aryloxy group or positioning a hydrogen-bonding solvent to assist the departure of the leaving group. An important finding revealed by the calculations is the flexibility of the ligand system that allows the Zn–Zn distance to expand from ∼3.6 Å in <b>1a</b> to over 5 Å in the transforming <b>2</b>:<b>1a</b> and <b>3</b>:<b>1a</b> complexes during the catalytic event

Trifunctional Metal Ion-Catalyzed Solvolysis: Cu(II)-Promoted Methanolysis of <i>N</i>,<i>N</i>‑bis(2-picolyl) Benzamides Involves Unusual Lewis Acid Activation of Substrate, Delivery of Coordinated Nucleophile, Powerful Assistance of the Leaving Group Departure

The methanolyses of Cu­(II) complexes of a series of <i>N</i>,<i>N</i>-bis­(2-picolyl) benzamides (<b>4a</b>–<b>g</b>) bearing substituents X on the aromatic ring were studied under _s^spH-controlled conditions at 25 °C. The active form of the complexes at neutral _s^spH has a stoichiometry of <b>4</b>:Cu­(II):(⁻OCH₃)­(HOCH₃) and decomposes unimolecularly with a rate constant <i>k</i>_<i>x</i>. A Hammett plot of log­(<i>k</i>_<i>x</i>) vs σ_<i>x</i> values has a ρ_<i>x</i> of 0.80 ± 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro and 4-methoxy derivatives, <b>4b</b>:Cu­(II):(⁻OCH₃)­(HOCH₃) and <b>4g</b>:Cu­(II):(⁻OCH₃)­(HOCH₃), in the plateau region of the _s^spH/log­(<i>k</i>_<i>x</i>) profiles in both CH₃OH and CH₃OD. Activation parameters for decomposition of these complexes are Δ<i>H</i>^⧧ = 19.1 and 21.3 kcal mol^–1 respectively and Δ<i>S</i>^⧧ = −5.1 and −2 cal K^–1 mol^–1. Density functional theory (DFT) calculations for the reactions of the Cu­(II):(⁻OCH₃)­(HOCH₃) complexes of <b>4a,b</b> and <b>g</b> (<b>4a</b>, X = 3,5-dinitro) were conducted to probe the relative transition state energies and geometries of the different states. The experimental and computational data support a mechanism where the metal ion is coordinated to the <i>N</i>,<i>N</i>-bis­(2-picolyl) amide unit and positioned so that it permits delivery of a coordinated Cu­(II):(⁻OCH₃) nucleophile to the CO in the rate-limiting transition state (TS) of the reaction. This proceeds to a tetrahedral intermediate <i><b>INT</b></i>, occupying a shallow minimum on the free energy surface with the Cu­(II) coordinated to both the methoxide and the amidic N. Breakdown of <i><b>INT</b></i> is a virtually barrierless process, involving a Cu­(II)-assisted departure of the bis­(2-picolyl)­amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism where it activates intramolecular nucleophilic attack on the CO group by coordination to an amidic N in the first step of the reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the second order rate constant for methoxide attack on <b>4b</b>, the computed reaction of CH₃O^– and <b>4b</b>:Cu­(II):(HOCH₃)₂ is accelerated by roughly 2.0 × 10¹⁶ times