Metal Ion-Promoted Leaving Group Assistance in the Solvolysis of Phosphate Esters, Amides, and Thioamides

Abstract

Toward the efficient solvolysis of phosphate esters and amides under mild conditions, many small-molecule metal-containing catalysts have been designed to activate the substrate toward metal-mediated nucleophilic addition. However, very few systems have been designed to also employ a metal ion to activate the leaving group (LG) toward departure. To this end, the following studies were undertaken to ascertain the magnitude and mechanism of metal ion-promoted leaving group assistance. The solvolysis of a specially-designed set of phosphate mono-, di-, and triesters, having a Cu(II)-complexed 2-phenanthrolyl group at the ortho-position of a departing phenoxide, was studied in water and ethanol under pH-controlled conditions at 25 °C. A combination of pH/rate profiles, solvent deuterium kinetic isotope effect (DKIE) values, and activation parameters were collected and compared to the results in methanol. While a detailed comparison of the activation parameters reveals complex trends due to changes in the reaction medium, the rate-accelerating effects of the Cu(II)-promoted leaving group assistance in all three solvents are substantial, ranging from 10^5 to 10^15 relative to their background reactions. The methanolysis of the Cu(II) complexes of a series of substituted N,N-bis(2-picolyl)benzamides was studied under sspH-controlled conditions at 25 °C. Hammett reaction constants, solvent DKIE values, activation parameters, and computational results describe a mechanism where the metal ion, coordinated to the N,N-bis(2-picolyl)amide unit, delivers a Cu(II)-coordinated methoxide to the carbonyl group in the rate-limiting transition state of the reaction. The metal ion appears to activate the substrate through coordination to the amide nitrogen, activate and deliver the nucleophile, and subsequently assist LG departure. Expanding upon this work revealed a common mechanism for the methanolysis and ethanolysis of the Ni(II), Zn(II), and Cu(II) complexes of N,N-bis(2-picolyl)-p-nitrobenzamide and N,N-bis((1H-benzimidazol-2-yl)methyl)-p-nitrobenzamide. Comparing the rate constants for the attack of alkoxide on the M(II)-complexed 4 nitro-substituted benzamides to those for the uncomplexed forms reveals accelerations ranging from 10^14 to 10^19. Finally, the palladacycle-promoted methanolysis of a series of thiobenzanilides with different LGs was studied under sspH-controlled conditions at 25 °C. The kinetic data indicate that two mechanisms are operative wherein either one or two catalysts effect cleavage depending on the nature of the LG.