carbonyl oxygen. This is a result of the overlap interactions between the HOMO lone pair on nitrogen and the LUMO of the carbon. However, due to the pyramidalization of the nitrogen and the distorted C-N bond, the degree of amide resonance stabilization is lowered, with respect to planar amides such as the β-lactam moiety that have aligned orbitals for overlap. Reactions Penams are reactive towards catalytic cleavage via hydrolysis because of the carbonyl carbon's propensity for nucleophilic attack. This is understood by its partial positive (electrophilic) character that results from the electron density being slightly withdrawn by the carbonyl oxygen atom and, consequently, the lack of conjugation between the nitrogen and carbonyl group. Although amide bonds are typically unreactive to cleavage because of its partial double bond character, the pyramidalization and C-N bond distortion make the amide bond in penams have a single bond character, which is more reactive to cleavage. Also, cleavage of the C-N bond is thermodynamically favorable, since opening of the β-lactam ring reduces ring strain. Catalyzed Cleavage Ring-opening of penams can be acid- or base- catalyzed hydrolysis. Under acidic conditions, the water acts as a nucleophile that attacks the electrophilic carbon of the carbonyl group. Under basic conditions, the hydroxide acts as the nucleophile. In enzymes, the hydroxyl group of a serine residue acts as the nucleophile. Regardless of which nucleophilic species that attacks the electrophilic carbon of the carbonyl group, the nucleophile binds, creating a tertiary carbon intermediate. Electrons are transferred from the C-N bond and onto the nitrogen atom which acts as the leaving group. As a result, the C-N bond is cleaved, forming a carboxylic acid and secondary amine. References Beta-lactamase inhibitors Sulfur heterocycles Nitrogen heterocycles Heterocyclic compounds with 2 rings Ketones