TwoN-(2-phenylethyl)nitroaniline derivatives as precursors for slow and sustained nitric oxide release agents

Abstract

Notwithstanding its simple structure, the chemistry of nitric oxide (NO) is complex. As a radical, NO is highly reactive. NO also has profound effects on the cardiovascular system. In order to regulate NO levels, direct therapeutic interventions include the development of numerous NO donors. Most of these donors release NO in a single high-concentration burst, which is deleterious. N-Nitrosated secondary amines release NO in a slow, sustained, and rate-tunable manner. Two new precursors to sustained NO-releasing materials have been characterized. N-[2-(3,4-Dimethoxyphenyl)ethyl]-2,4-dinitroaniline, C16H17N3O6, (I), crystallizes with one independent molecule in the asymmetric unit. The adjacent amine and nitro groups form an intramolecular N-H...O hydrogen bond. The anti conformation about the phenylethyl-to-aniline C-N bond leads to the planes of the arene and aniline rings being approximately perpendicular. Molecules are linked into dimers by weak intermolecular N-H...O hydrogen bonds such that each amine H atom participates in a three-center interaction with two nitro O atoms. The dimers pack so that the arene rings of adjacent molecules are not parallel and π-π interactions do not appear to be favored. N-(4-Methylsulfonyl-2-nitrophenyl)-L-phenylalanine, C16H16N2O6S, (II), with an optically active center, also crystallizes with one unique molecule in the asymmetric unit. The L enantiomer was established via the configuration of the starting material and was confirmed by refinement of the Flack parameter. As in (I), there is an intramolecular N-H...O hydrogen bond between adjacent amine and nitro groups. The conformation of the molecule is such that the arene rings display a dihedral angle of ca 60°. Unlike (I), molecules are not linked via intermolecular N-H...O hydrogen bonds. Rather, the carboxylic acid H atom forms a classic, approximately linear, O-H...O hydrogen bond with a sulfone O atom. Pairs of molecules related by twofold rotation axes are linked into dimers by two such interactions. The packing pattern features a zigzag arrangement of the arene rings without apparent π-π interactions. These structures are compared with reported analogues, revealing significant differences in molecular conformation, intermolecular interactions, and packing that result from modest changes in functional groups. The structures are discussed in terms of potential NO-release capability.

Models for potential dendritic nitric oxide donors: crystal structures of two 2-nitroanilino precursors and nitric oxide-release behavior of the nitrosated derivatives

“…The structure is thus composed of step-shaped molecules and essentially flat molecules. Both molecules show intramolecular N-HÁ Á ÁO hydrogen bonding between the ortho amine and nitro groups (Table 2) to form a six-membered ring that is typically observed in molecules with these functional groups adjacent to each other (Badour et al, 2016;Helttunen et al, 2013). The arene ring in the gauche molecule is rotated modestly relative to the butyl chain [torsion angle C8-C3-N1-C1 = 8.0 (2) ], while the ring in the anti molecule is almost perfectly aligned with the chain [torsion angle C18-C13-N11-C11 = À0.4 (2) ], further contributing to the flatness of the latter.…”