Mild, rapid and selective alcoholysis of terpyridine-appended amide substrates by Cu2+-catalysis: protonation state and reactivity of the complex

An amide bond of a terpyridine-appended substrate, 6-(L-phenylalanylamino)-2,2′:6′,2″-terpyridine (2a), was cleaved to yield phenylalanine methyl ester quantitatively in the presence of catalytic amounts of Cu2+ not only in methanol but also in aqueous methanol at 30 °C. The reaction proceeds via formation of an N3O (three terpyridine nitrogens and one carbonyl oxygen) type 1:1 metal complex 2a-Cu2+. From spectral titration, the structure of the 2a-Cu2+ complex was confirmed to have three different protonation states, i.e., A (non-deprotonated amide with α-ammonium), D1 (deprotonated-amide with α-ammonium) and D2 (deprotonated-amide with α-amino) states. Among them, the complex in the D2 state was exclusively responsible for the observed mild, rapid and selective alcoholysis, showing the first-order rate constant of 6 × 10−3 s−1 or half-decay time of 2 min in methanol at 30 °C. Acidity of the amide proton was found to be higher than that of the ammonium proton in the complex, allowing formation of the highly reactive amide-deprotonated D2 state in methanol even without addition of external bases. Factors contributing to the high reactivity of the complex were discussed.