Stephen A. Glover

N-alkoxy-n-acylnitrenium ions in intramolecular aromatic addition reactions

Abstract N-alkoxy-N-acylnitronium ions are generated by treatment of N-alkoxy-N-cohloroamides with silver ions in ethereal solvents. These intermediates readily cyclise onto aromatic nuclei on alkozy side-chains to give benzoxazines and benzoxazepines and on the acyl side-chains to give γ, δ and ϵ benzolactams. Spirane products are formed by ipso addition When a 4-methoxy substituent ia present on the side-chain aromatic rings. The yields and regioselectivities of these reactions have been ascribed to different transition structures for cyclisation onto the acyl and alkoxy side-chains which involve respectively an exocyolic and endocyclic N-0 π-bond. Evidence for this exeptionally high π-bond character has been obtained from MNDO calculations which predict a π-bond order of 0.9 and a rotational barrier of 29.7 kcalmol-1

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 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.

MNDO properties of heteroatom and phenyl substituted nitrenium ions

Abstract MNDO calculations Indicate that -NH2,-PH2,-SH,-OH and phenyl substituted nitrenium ions and N-formyl nitrenium ions have singlet ground states of comparable stability and ease of formation. Ab initio calculations at 6-31G** level yield similar results to MNDO for NH2+, and its -NH2,-PH2,-SH, and -OH substituted derivatives.

HERON rearrangement of N,N′-diacyl-N,N′-dialkoxyhydrazines — a theoretical and experimental study

Abstract Ab initio calculations at the B3LYP/6–31G* level on N -methoxy- N -dimethylaminoformamide and its rearrangement to methyl formate and 1,1-dimethyldiazene through the HERON reaction, have been carried out in conjunction with an experimental study of the HERON reactions of N , N ′-diacyl- N , N ′-dialkoxyhydrazines. Substituent effects are in accord with the theoretical properties of the transition state and point to an anomerically driven process in which donor groups on the anomeric nitrogen and withdrawing groups on the migrating alkoxy oxygen facilitate the rearrangement process.

N-acetoxy-N-alkoxyamides: a new class of nitrenium ion precursors which are mutagenic

Abstract N-chloro-O-alkylbenzohydroxamates react with silver acetate in ether giving N-acetoxy-N-alkoxybenzamides which, by analogy with N,O-diacyl-N-arylhydroxylamines, have been shown to be mutagenic in the Ames test.

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

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.

Solvolysis and mutagenesis of n-acetoxy-n-alkoxybenzamides — evidence for nitrenium ion formation

Abstract Mutagenic N-acetoxy-N-butoxybenzamides undergo acid catalysed solvolysis in acetonitrile/water. Kinetic data and a Hammett σ + correlation (ϱ=−1.4) indicate nitrenium ion formation in the rate determining step. Levels of mutagenicity mirror the rates of solvolysis suggesting nitrenium ion involvement.

Hindered ester formation by SN2 azidation of N-acetoxy-N-alkoxyamides and N-alkoxy-N-chloroamides—novel application of HERON rearrangements

Treatment of N-acetoxy-N-alkoxyamides or N-alkoxy-N-chloroamides with sodium azide in aqueous acetonitrile results in SN2 displacement of chloride and the formation of reactive N-alkoxy-N-azidoamides. The reaction with N-acetoxy-N-benzyloxybenzamide has been studied kinetically (k294 = 2 L mol−1 s−1) and azidation of N-formyloxy-N-methoxyformamide has been modeled computationally at the pBP/DN*//HF/6-31G* level of theory. The anomeric amides N-alkoxy-N-azidoamides decompose intramolecularly and spontaneously to esters and two equivalents of nitrogen. This extremely exothermic process facilitates the formation, in excellent yields, of highly hindered esters.

Structures of N,N-Dialkoxyamides: Pyramidal Anomeric Amides with Low Amidicity

The first X-ray structures of two anomeric N,N-dialkoxyamides (2 and 3) have been obtained, which confirm that they are highly pyramidalized at nitrogen and have long N-CO bonds, a characteristic of other anomeric amides and a consequence of drastically reduced amidicity. The crystals also demonstrate chirality at the amide nitrogen in the solid state. The structures are well-predicted by density functional calculations using N,N-dimethoxyacetamide as a model. The amidicity of N,N-dimethoxyacetamide has been estimated by two independent methods, COSNAR and a new transamidation method, which give almost identical resonance stabilization energies of -8.6 kcal mol(-1) and only 47% that of N,N-dimethylacetamide computed at the same level. The total destabilization is composed of a resonance and an inductive contribution, which we have evaluated separately. The electronegative oxygens at nitrogen are responsible for localization of the nitrogen lone pair on the amide nitrogen, a factor that contributes to a loss of resonance over and above the impact of pyramidalization at nitrogen, as well as the fact that N,N-dimethoxyacetamide is predicted to protonate on the carbonyl oxygen in preference to nitrogen.

Molecular orbital studies of novel N to C migrations in N,N-bisheteroatom-substituted amides—HERON rearrangements

Bisheteroatom-substituted amides (R–CO–NXY) can undergo a novel rearrangement of the more electronegative atom from nitrogen to the carbonyl carbon producing acyl derivatives (R–CO–X) and substituted nitrenes (N–Y). Such reactions have been observed chemically. AM1 molecular orbital calculations on N-substituted acetamides support the concerted nature of this process and predict that amino substituents (Y = NR2) promote the rearrangement of similarly or more electronegative nitrogen substituents (X = NR2, Cl, OR). Migration appears to be driven by an anomeric effect involving interaction between the lone pair on Y and the X–N σ* orbital. Favourable transiton states display a significant increase in N–Y double bond character, negative charge on the migrating substituent and little RCO–N heterolysis. 6–31G*ab initio calculations on migration of the hydroxy group in N-amino-N-hydroxyformamide largely accord with the AM1 findings for this model compound.