Reliable Determination of Amidicity in Acyclic Amides and Lactams

Abstract

Two independent computational methods have been used for determination of amide resonance stabilization and amidicities relative to N,N-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 N,N-dimethylacetamide and the target amide using an isodesmic trans-amidation process and is calibrated relative to 1-aza-2-adamantanone with zero amidicity and N,N-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 C-N bonds. Monocyclic lactams are predicted to have amidicities at least as high as N,N-dimethylacetamide, and the β-lactam system is planar with greater amide resonance than that of N,N-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 N,N-dimethylacetamide.

Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

“…In a recent publication, we outlined two concurring isodesmic methods for estimating the amidicity of amides and lactams [4]. Carbonyl substitution, nitrogen atom replacement (COSNAR), developed by Greenberg evaluates the energy stabilisation when the target amide is generated from corresponding ketone and amine according to isodesmic Equation (1) [57,58,59].…”

“…RE by both methods, the negative of the traditional representation of resonance stabilisation energy, should correlate [4,30,33,34,61,62] and RE as a percentage of −76.0 kJ mol −1 (or −77.5 kJ mol −1 in the case of COSNAR) yields the amidicity relative to N , N -dimethylacetamide 1 (by definition 100%).…”

“…Computational modelling of N–C(O) rotation and nitrogen pyramidalisation in N , N -dimethylacetamide 1 , at the B3LYP/6-31G(d) level, illustrates the energetic changes (Figure 3) [4]. Distortion of the amide linkage can be quantified by Winkler–Dunitz parameters χ and τ, where χ = 60° for a fully pyramidal nitrogen, and τ = 90° for a completely twisted amide where the lone pair orbital on nitrogen is orthogonal to the C2p z orbital [5,6].…”

Electrospray Ionization (ESI) Fragmentations and Dimethyldioxirane Reactivities of Three Diverse Lactams Having Full, Half, and Zero Resonance Energies

“…Since this last parameter is usually quite small, 30 a three-dimensional plot of energy versus τ and χ N is quite useful. 5 There can be a delicate balance between protonation on oxygen or nitrogen depending on these parameters. For example, 1-azabicyclo-[3.2.2]nonan-2-one favors methylation on nitrogen ( 4 ), while slightly less distorted 1-azabicyclo-[3.3.2]decan-2-one favors methylation on oxygen ( 5 ).…”

Twisted amide electrophiles enable cyclic peptide sequencing

“…14 Aziridine amides are ambident electrophiles, meaning that they can partake in both S N 2 and transacylation reactions (Fig. 16 As reactive intermediates, aziridine amides have been primarily used in S N 2 reactions with soft nucleophiles. 15 This dual electrophilicity is Fig.…”