Reliable Determination of Amidicity in Acyclic Amides and Lactams

Two independent computational methods have been used for determination of amide resonance stabilization and amidicities relative to <i>N</i>,<i>N</i>-dimethylacetamide for a wide range of acyclic and cyclic amides. The first method utilizes carbonyl substitution nitrogen atom replacement (COSNAR). The second, new approach involves determination of the difference in amide resonance between <i>N</i>,<i>N</i>-dimethylacetamide and the target amide using an isodesmic <i>trans-</i>amidation process and is calibrated relative to 1-aza-2-adamantanone with zero amidicity and <i>N</i>,<i>N</i>-dimethylacetamide with 100% amidicity. Results indicate excellent coherence between the methods, which must be regarded as more reliable than a recently reported approach to amidicities based upon enthalpies of hydrogenation. Data for acyclic planar and twisted amides are predictable on the basis of the degrees of pyramidalization at nitrogen and twisting about the <i>C</i>–<i>N</i> bonds. Monocyclic lactams are predicted to have amidicities at least as high as <i>N</i>,<i>N</i>-dimethylacetamide, and the β-lactam system is planar with greater amide resonance than that of <i>N</i>,<i>N</i>-dimethylacetamide. Bicyclic penam/em and cepham/em scaffolds lose some amidicity in line with the degree of strain-induced pyramidalization at the bridgehead nitrogen and twist about the amide bond, but the most puckered penem system still retains substantial amidicity equivalent to 73% that of <i>N</i>,<i>N</i>-dimethylacetamide