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

Two new Pb­(II) complexes of the amide-appended
nitrogen/sulfur
epppa (N-((2-ethylthio)­ethyl)-N-((6-pivaloylamido-2-pyridyl)­methyl)-N-((2-pyridyl)­methyl)­amine) chelate ligand, [(epppa)­Pb­(NO3)2] (4-NO3) and [(epppa)­Pb­(ClO4)2] (4-ClO4), were prepared and characterized. In the
solid state, 4-NO3 exhibits κ5-epppa chelate ligand coordination as well as the coordination
of two bidentate nitrate ions. In acetonitrile, 4-NO3 is a 1:1 electrolyte with a coordinated NO3–, whereas 4-ClO4 is a 1:2 electrolyte. Treatment of 4-ClO4 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 (3-ClO4). 1H NMR kinetic
studies of the amide methanolysis reactions of 4-ClO4 and 3-ClO4 as a function of temperature revealed free energies of activation
of 21.3 and 24.5 kcal/mol, respectively. The amide methanolysis reactions
of 4-ClO4 and 3-ClO4 differ in terms of the effect of the concentration
of methanol (saturation kinetics for 4-ClO4; second-order behavior for 3-ClO4), the observation of a small solvent kinetic
isotope effect (SKIE) only for the reaction of the Zn­(II)-containing 3-ClO4, 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 4-ClO4 and 3-ClO4, indicate that the Zn­(II)-containing 3-ClO4 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 4-ClO4 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 4-ClO4 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 3-ClO4.