Synthesis, Structure, and Conformational Dynamics of Bridgehead-Substituted Nitrosamines. Di-1-adamantylnitrosamine and Di-1-norbornylnitrosamine

Abstract

The synthesis of two bridgehead-substituted nitrosamines, di-1-adamantylnitrosamine (1) and di-1-norbornylnitrosamine (2), is described, and their solid state crystal structures are reported. Large bridgehead substituents increase the NNO angle of the nitrosamine (compared to that found for dimethylnitrosamine) without deconjugating the NNO pi system significantly. This structural change correlates with a red-shifted optical absorption, a diminished N,N rotational barrier, and a greater ease of oxidation of these hindered nitrosamines than is observed for dimethylnitrosamine. The electronic basis of these structure/function correlations is examined. It is concluded that 1 is more strained than N-nitroso-2,2,6,6-tetramethylpiperidine (3) which is more strained than 2 and that a raised (in energy) NO n orbital is primarily responsible for the extreme properties of the former.

Ab initio and DFT conformational study on nitrosamine (H2N–N=O) and N-Nitrosodimethylamine [(CH3)2N–N=O]

“…The molecular structures of N-nitrosamines exert a pronounced influence on the bioactivity of this class of compounds [11,[16][17][18][19]. For instance, within a set of 235 different nitrosamines tested for carcinogenic activity by Preussmann and Stewart [11], only a few were noncarcinogenic, and the presence of an N-t-butyl group is the common feature of this subset.…”

“…Sarker et al [19] have prepared sterically hindered bridgehead-substituted N-alkyl nitrosamines, such that the NNO angle of the nitrosamine is increased (as compared to that of N-Nitrosodimethylnitrosamine) but with no significant deconjugation of the NNO p system. It has been observed that this structural change is accompanied by and correlates with a red-shift in the optical absorption spectrum, a decrease in the N-N rotational barrier, and an increase in the oxidation potential of these hindered nitrosamines, as compared with that of N-Nitrosodimethylnitrosamine [19].…”

“…Sarker et al [19] have prepared sterically hindered bridgehead-substituted N-alkyl nitrosamines, such that the NNO angle of the nitrosamine is increased (as compared to that of N-Nitrosodimethylnitrosamine) but with no significant deconjugation of the NNO p system. It has been observed that this structural change is accompanied by and correlates with a red-shift in the optical absorption spectrum, a decrease in the N-N rotational barrier, and an increase in the oxidation potential of these hindered nitrosamines, as compared with that of N-Nitrosodimethylnitrosamine [19]. Ohwada et al have found a correlation between the rotational barriers of several aliphatic and aromatic N-nitrosamines and their ability to act as nitric oxide or nitrosonium ion donors [16,17], which is particularly relevant as these two resulting species are associated with important biological effects and outcome (Ref.…”

Hydroacridines: Part 33. An experimental and DFT study of the 13C NMR chemical shifts of the nitrosamines derived from the six stereoisomers of tetradecahydroacridine

“…Owing to the various reaction capabilities of their functional group, nitrosamines became valued intermediates in syntheses of numerous organic compounds, and thus, their chemical, biochemical, photochemical, and physical properties are subject of continuing research efforts. Some of the most important advances in nitrosamines structural chemistry were achieved by workers using the methods of 1 H, 13 C, and 15 N NMR spectroscopy. The restricted rotation about the N─N bond in nitrosamines was documented and rationalized by the interaction between the electron lone pair of the amino nitrogen and the π electrons of the ─N═O group (n N ―π NO * conjugation) that confers a partial double‐bond character to these N─N bonds and a preference for a planar geometry (or very nearly so) to the amino nitrogens .…”

“…The energy barriers to the restricted N─N rotation have been determined for a considerable number of nitrosamines, and values ranging from 51 up to 100 kJ mol −1 were reported. It has been noted that nitrosamines with the bulkiest alkyl substituents at the amino nitrogen atom show the lowest energy rotational barriers (within 51–84 kJ mol −1 ), whereas those bearing small substituents typically exhibit the highest rotational barriers (95–100 kJ mol −1 This kind of behavior has been rationalized as follows: In nitrosamines with bulky substituents (large, or highly branched in α‐positions), because of the strong steric interaction between the space demanding >N─N═O system and the bulky alkyl substituents at the amino nitrogen, either the ─N═O group, or the N ‐alkyl group, or both of them will undergo deviation from coplanarity, accompanied, among others, by weakened n N ―π NO * conjugation and diminished N─N rotational barrier. In the typical nitrosamines containing small substituents, however, in the absence of any steric strain, the coplanarity of the (C‐α) 2 N─N═O system, the n N ―π NO * conjugation, and together with them, the high N─N rotational barriers are preserved.…”