Crystal structures and properties of mutagenic N-acyloxy-N-alkoxyamides — “most pyramidal” acyclic amides

Abstract

X-Ray data for two N-acyloxy-N-alkoxyamides, a class of direct-acting mutagens, indicate extreme pyramidalisation at the amide nitrogen in keeping with spectroscopic and theoretically determined properties of amides with bisoxosubstitution at nitrogen. The combined electronegativity of two oxygens leads to average angles at nitrogen of 107.8 and 108.1 degrees and [chiN] of 66 degrees and 65 degrees. The sp3 nature of nitrogen results in negligible amide resonance as evidenced by long N-C(O) bonds, high IR carbonyl stretch frequencies, carbonyl 13C NMR data and very low amide isomerisation barriers. In addition, conformations in the solid state support a strong n(O)-sigma*(NOAc), anomeric interaction as predicted by molecular orbital theory. HF/6-31G* calculations on formamide, N-methoxyformamide and N-formyloxy-N-methoxyformamide support these findings.

The HERON reaction — Origin, theoretical background, and prevalence

“…We recently published the structures of the "most pyramidal" amides, both N-acyloxy-Nalkoxyamides, which verify the conformational effects previously described (Fig. 3a) (16). Not only do they exhibit highly pyramidal nitrogens (avg.…”

“…3b). Both structures exhibit a conformational preference that clearly optimizes either the n O -σ NO * or the n N -σ NO * overlap (15,16).…”

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

“…We named this class ‘anomeric amides’ on account of the pronounced anomeric effects that can and do occur between the heteroatoms [26,27,28,29,30,31,32,33,34,35]. However, the physical, theoretical, and chemical properties of various congeners differ from those of conventional primary, secondary, and tertiary alkylamides.…”

“…The data in Table 1 shows that as the combined electron demands of X and Y increase, N–C(O) bond length and pyramidalisation at nitrogen both increase. The reported average N–C(O) bond length in acyclic amides is 1.359 Å (median 1.353 Å), generated from Cambridge Structural Database (CSD) [29,63], which is significantly shorter than the average 1.418 Å from these seven X-ray structures. While the (N)C=O bond (average 1.207 Å) contracts slightly compared to simple acyclic amides (1.23 Å), there is little to no correlation seen between change in (N)C=O bond length and degree of lone pair dislocation; this may be attributed to bias towards carbon in the LUMO (Figure 1) [2,26,35,64].…”

“…X-ray structures for ( a ) N -ethoxy- N -methoxy-4-nitrobenzamide 5a [33], ( b ) N -methoxy- N -(4-nitrobenzyloxy)benzamide 5b [33], ( c ) N -acetoxy- N -methoxy-4-nitrobenzamide 7 [65], ( d ) N -benzoyloxy- N -(4- tert -butylbenzyloxy)benzamide 6b [29], ( e ) N -(4- tert -butylbenzoyloxy)- N -(4- tert -butylbenzyloxy)-4- tert -butylbenzamide 6a [29], ( f ) N- chloro- N -methoxy-4-nitrobenzamide 9 [65], and ( g ) N , N ′-4-chlorobenzoyl- N , N ′-diethoxyhydrazine 8 [32]. …”