β-Lactams are found in the penicillin family of antibiotics. It has been shown that azlactones react with imines to form β-lactams. In the currently accepted mechanism of this reaction the azlactone tautomerizes into a münchnone, which then isomerizes into a ketene intermediate. We probed this mechanism using DFT computational methodology [M05-2X/6-311+G(2d,p)]. In addition to the currently accepted mechanism, alternative mechanisms were also studied. They include mechanisms that involve direct addition of an imine to the azlactone. It was found that the münchnone was 13 kcal/mol and the ketene was 20 kcal/mol higher in energy than the azlactone. The intermediates involved in the direct addition pathway were found to be higher in energy that either the azlactone or ketene. However, if the azlactone is protonated the reaction could proceed with the rate-determining barrier of 16 kcal/mol without involvement of a ketene intermediate. We propose that a protonated azlactone is viable under many experimental conditions that give rise to β-lactams. Additionally, these studies suggest broader mechanistic implications for Lewis acid-catalyzed reactions of azlactones. The effect of substituents on the energetics of the azlactone, münchnone and ketene was also investigated.

Is ketene an intermediate in the addition of imines to azlactone to form a β-lactam?

249th National Meeting (2015)

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