Cu(II)-Ion-Catalyzed Solvolysis of <i>N,N-</i>Bis(2-picolyl)ureas in Alcohol Solvents: Evidence for Cleavage Involving Nucleophilic Addition and Strong Assistance of Bis(2-picolyl)amine Leaving Group Departure

The kinetics and products for solvolysis of <i>N</i>-<i>p</i>-nitrophenyl-<i>N</i>′,<i>N</i>′-bis­(pyridin-2-ylmethyl) urea (<b>7a</b>), <i>N</i>-methyl-<i>N</i>-<i>p</i>-nitrophenyl-<i>N</i>′,<i>N</i>′-bis­(pyridin-2-yl methyl) urea (<b>7b</b>), and <i>N</i>-phenyl-<i>N</i>′,<i>N</i>′-bis­(pyridin-2-yl-methyl) urea (DPPU) (<b>7c</b>) promoted by Cu­(II) ion in methanol and ethanol were studied under _s^spH-controlled conditions at 25 °C. Methanolysis and ethanolysis of these substrates proceeds rapidly at a 1:1 ratio of substrate:metal ion, the half-times for decomposition of the Cu­(II):<b>7a</b> complexes being ∼150 min in methanol and 15 min in ethanol. In all cases, the reaction products are the Cu­(II) complex of bis­(2-picolyl)­amine and the <i>O</i>-methyl or <i>O</i>-ethyl carbamate of the parent aniline, signifying that the point of cleavage is the bis­(2-picolyl)NCO bond. Reactions of the Cu­(II):<b>7b</b> complexes in each solvent proceed about 3–5 times slower than their respective Cu­(II):<b>7a</b> complexes, excluding an elimination mechanism that proceeds through an isocyanate which subsequently adds alcohol to give the observed products. The reactions also proceed in other solvents, with the order of reactivity ethanol > methanol >1-propanol >2-propanol > acetonitrile (with 0.2% methanol) > water spanning a range of 150-fold. The mechanism of the reactions is discussed, and the reactivity and mode of cleavage are compared with that of the M­(II)-promoted ethanolytic cleavage of a mono-2-picolyl derivative, <i>N</i>-<i>p</i>-nitrophenyl-<i>N</i>′-(pyridin-2-yl-methyl) urea (<b>4a</b>), which had previously been shown to cleave at the aniline N–CO bond. The large estimated acceleration of the rate of attack of ethoxide on <b>7b</b> of at least 2 × 10¹⁶ provided by associating Cu­(II) with the departing group in this urea is discussed in terms of a trifunctional role for the metal ion involving Lewis acid activation of the substrate, intramolecular delivery of a Cu­(II)-coordinated ethoxide, and metal-ion-assisted leaving group departure

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

Rapid Ni, Zn, and Cu Ion-Promoted Alcoholysis of <i>N</i>,<i>N-</i>Bis(2-picolyl)- and <i>N</i>,<i>N-</i>Bis((1<i>H</i>‑benzimidazol-2-yl)methyl)‑<i>p</i>‑nitrobenzamides in Methanol and Ethanol

The methanolysis and ethanolysis of the Ni­(II), Zn­(II), and Cu­(II) complexes of <i>N</i>,<i>N</i>-bis­(2-picolyl)-<i>p</i>-nitrobenzamide (<b>1</b>) and <i>N</i>,<i>N</i>-bis­((1<i>H</i>-benzimidazol-2-yl)­methyl)-<i>p</i>-nitrobenzamide (<b>2</b>) were studied under pH-controlled conditions at 25 °C. Details of the mechanism were obtained from plots of the <i>k</i>_obs values for the reaction under pseudo-first-order conditions as a function of [M²⁺]. Such plots give saturation kinetics for the Cu­(II)-promoted reactions of <b>1</b> and <b>2</b> in both solvents, the Zn­(II)-promoted reaction of <b>1</b> in methanol, and the Zn­(II)- and Ni­(II)-promoted reactions of <b>2</b> in methanol and ethanol. Logs of the maximal observed rate constants obtained from the latter plots, (<i>k</i>_obs^max), when plotted versus _s^spH, are curved downward only for the Cu­(II) complexes of <b>1</b> and <b>2</b> in both solvents and the Zn­(II) complex of <b>1</b> in methanol. Despite differences in the metal-binding abilities and p<i>K</i>_a values for formation of the active form, there is a common reaction mechanism, with the active form being <b>1</b>:M­(II):(^<b>–</b>OR) and <b>2</b>:M­(II):(^<b>–</b>OR), where M­(II):(^<b>–</b>OR) is the metal-bound alkoxide. The acceleration provided by the metal ion is substantial, being 10¹⁴–10¹⁹ relative to the <i>k</i>₂^¯OMe value for the alkoxide-promoted alcoholysis of the uncomplexed amide

Cu(II)-Promoted Methanolysis of <i>N</i>,<i>N</i>-Dipicolylacetamide. Multistep Activation by Decoupling of >N̈–CO Resonance via Cu(II)–N Binding, Delivery of the Cu(II):(⁻OCH₃) Nucleophile, and Metal Ion Assistance of the Departure of the Leaving Group

The methanolysis of the Cu­(II) complex of <i>N</i>-acetyl-<i>N</i>,<i>N</i>-bis­(2-picolyl)­amine (<b>2</b>) was investigated by a kinetic study as a function of pH in methanol at 25 °C and computationally by DFT calculations. The active species is the basic form of the complex (<b>3</b>⁻), or (<b>1</b>:Cu­(II))­(⁻OCH₃)­(HOCH₃)), and the rate constant for its solvolysis is <i>k</i>^max = 1.5 × 10^–4 s^–1. The mechanism involves Cu­(II) binding to the amide N lone pair, decoupling it from >N–CO resonance, concomitant with Cu­(II):(⁻OCH₃) delivery to the adjacent >N–CO unit, followed by Cu­(II)-assisted departure of the <i>N</i>,<i>N</i>-bis­(2-picolyl)­amide from a tetrahedral intermediate

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