Pb(II)-Promoted Amide Cleavage: Mechanistic Comparison to a Zn(II) Analogue

Two new Pb­(II) complexes of the amide-appended nitrogen/sulfur epppa (<i>N</i>-((2-ethylthio)­ethyl)-<i>N</i>-((6-pivaloylamido-2-pyridyl)­methyl)-<i>N</i>-((2-pyridyl)­methyl)­amine) chelate ligand, [(epppa)­Pb­(NO₃)₂] (<b>4-NO</b>_<b>3</b>) and [(epppa)­Pb­(ClO₄)₂] (<b>4-ClO</b>_<b>4</b>), were prepared and characterized. In the solid state, <b>4-NO</b>_<b>3</b> exhibits κ⁵-epppa chelate ligand coordination as well as the coordination of two bidentate nitrate ions. In acetonitrile, <b>4-NO</b>_<b>3</b> is a 1:1 electrolyte with a coordinated NO₃^–, whereas <b>4-ClO</b>_<b>4</b> is a 1:2 electrolyte. Treatment of <b>4-ClO</b>_<b>4</b> with 1 equiv Me₄NOH·5H₂O in CH₃CN:CH₃OH (3:5) results in amide methanolysis in a reaction that is akin to that previously reported for the Zn­(II) analogue [(epppa)­Zn]­(ClO₄)₂ (<b>3-ClO</b>_<b>4</b>). ¹H NMR kinetic studies of the amide methanolysis reactions of <b>4-ClO</b>_<b>4</b> and <b>3-ClO</b>_<b>4</b> as a function of temperature revealed free energies of activation of 21.3 and 24.5 kcal/mol, respectively. The amide methanolysis reactions of <b>4-ClO</b>_<b>4</b> and <b>3-ClO</b>_<b>4</b> differ in terms of the effect of the concentration of methanol (saturation kinetics for <b>4-ClO</b>_<b>4</b>; second-order behavior for <b>3-ClO</b>_<b>4</b>), the observation of a small solvent kinetic isotope effect (SKIE) only for the reaction of the Zn­(II)-containing <b>3-ClO</b>_<b>4</b>, and the properties of an initial intermediate isolated from each reaction upon treatment with Me₄NOH·5H₂O. These experimental results, combined with computational studies of the amide methanolysis reaction pathways of <b>4-ClO</b>_<b>4</b> and <b>3-ClO</b>_<b>4</b>, indicate that the Zn­(II)-containing <b>3-ClO</b>_<b>4</b> initially undergoes amide deprotonation upon treatment with Me₄NOH·5H₂O. Subsequent amide protonation from coordinated methanol yields a structure containing a coordinated neutral amide and methoxide anion from which amide cleavage can then proceed. The rate-determining step in this pathway is either amide protonation or protonation of the leaving group. The Pb­(II)-containing <b>4-ClO</b>_<b>4</b> instead directly forms a neutral amide-containing, epppa-ligated Pb­(II)–OH/Pb­(II)-OCH₃ equilibrium mixture upon treatment with Me₄NOH·5H₂O in methanol. The rate-determining step in the amide methanolysis pathway of <b>4-ClO</b>_<b>4</b> is nucleophilic attack of the Pb­(II)-OCH₃ moiety on the coordinated amide. Overall, it is the larger size of the Pb­(II) center and the availability of coordination positions that enable direct formation of a Pb­(II)–OH/Pb­(II)-OCH₃ mixture versus the initial amide deprotonation identified in the reaction of the Zn­(II)-containing <b>3-ClO</b><sub><b>4</b>