Relative Substituent Effects on Alkaline Solvolysis of β-Lactams (2-Azetidinones) and Amides

Abstract

The effect of aliphatic and aromatic substituents, in the 1- and 3-positions of β-lactams, on the rate of solvolysis were examined and compared to analogous substituent effects in the model linear amides. It was found that substituent effects in the β-lactams could be quantitated using the Taft equation, and that a greater sensitivity to polar effects exists in the β-lactams as compared to the model linear amides. In addition, for single substituents in the 1- and 3-positions of the lactams, there is less steric influence on the rate of solvolysis as compared to linear amides. The mechanism of alkaline hydrolysis of these β-lactams appears to be the rate-limiting attack of hydroxide ion at the carbonyl carbon of the amide group and not the breakdown of an ionized tetrahedral intermediate as has been proposed for γ-lactams. Hydrolytic studies on β-lactams at 80° yield a different pathway of degradation, because deamination of the amino acid appears to be rate limiting; thus, elevated temperature studies on β-lactams should be carried out with caution. Finally, it is concluded that β-lactams are not unusually stable in their reactivity toward nucleophiles, such as hydroxide and methoxide ions, and their lability closely follows the parent linear amides.