Trifunctional Metal Ion-Catalyzed Solvolysis: Cu(II)-Promoted Methanolysis of N,N-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 N,N-bis(2-picolyl) benzamides (4a-g) bearing substituents X on the aromatic ring were studied under (s)(s)pH-controlled conditions at 25 degrees C. The active form of the complexes at neutral (s)(s)pH has a stoichiometry of 4:Cu(II): (-OCH3)(HOCH3) and decomposes unimolecularly with a rate constant k(x). A Hammett plot of log(k(x)) vs sigma(x) values has a rho(x) 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, 4b:Cu(II):(-OCH3)(HOCH3) and 4g:Cu(II):(-OCH3)(HOCH3), in the plateau region of the (s)(s)pH/log(k(x)) profiles in both CH3OH and CH3OD. Activation parameters for decomposition of these complexes are Delta H-double dagger = 19.1 and 21.3 kcal mol(-1) respectively and Delta S-double dagger = -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 4a,b and g (4a, 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 N,N-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 INT, occupying a shallow minimum on the free energy surface with the Cu(II) coordinated to both the methoxide and the amidic N. Breakdown of INT 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 4b, the computed reaction of CH3O- and 4b:Cu(II):(HOCH3)(2) is accelerated by roughly 2.0 x 10(16) times.