Cu(II)-catalyzed transformation of benzylpenicillin revisited: the overlooked oxidation

Penicillins, a class of widely used β-lactam antibiotics, are known to be susceptible to catalyzed hydrolysis by metal ions such as Cu(II). However, new results in this study strongly indicate that the role of Cu(II) is not merely a hydrolysis catalyst but also an oxidant. When benzylpenicillin (i.e., penicillin G (PG)) was exposed to Cu(II) ion at an equal molar ratio and pH 7, degradation of PG occurred rapidly in the oxygen-rich solution but gradually slowed down to a halt in the oxygen-limited solution. In-depth studies revealed that Cu(II) catalyzed hydrolysis of PG to benzylpenicilloic acid (PA) and oxidized PA to yield phenylacetamide and other products. The availability of oxygen played the role in reoxidizing Cu(I) back to Cu(II), which sustained fast degradation of PG over time. The overall reaction was also influenced by pH, with Cu(II)-catalyzed hydrolysis of PG occurring throughout pH 5, 7 and 9, while Cu(II) oxidation of PA occurring at pH 7 and 9. Note that the potential of Cu(II) to oxidize penicillins was largely overlooked in the previous literature, and catalyzed hydrolysis was frequently assumed as the only reaction. This study is among the first to identify the dual roles of Cu(II) in the entire degradation process of PG and systematically investigate the overlooked oxidation reaction to elucidate the mechanism. The new mechanistic knowledge has important implications for many other β-lactam antibiotics for their interactions with Cu(II), and significantly improves the ability to predict the environmental fate and transformation products of PG and related penicillins in systems where Cu(II) species are also present.