Chemistry of the Diazeniumdiolates. 3. Photoreactivity

Abstract

We have found O(2)-substituted diazeniumdiolates, compounds of structure R(2)N-N(O)=NOR' that are under development for various possible pharmaceutical uses, to be rather photosensitive. With R = ethyl and R' = methyl, benzyl, or 2-nitrobenzyl, the observed product distributions suggest that two primary pathways are operative. A minor pathway involves the extrusion of nitrous oxide (N(2)O) with simultaneous generation of R(2)N(*) and R'O(*), which may then form amines, aldehydes, and alcohols. The major reaction pathway is an interesting photochemical cleavage of the N=N bond to form a nitrosamine (R(2)NN=O) and an oxygen-substituted nitrene (R'ON). The intermediacy of the O-nitrene was inferred from the production of abundant oxime, via rearrangement of the O-nitrene to a C-nitroso compound (R'ON --> O=NR'), and subsequent tautomerization to the more stable oxime. Involvement of the O-nitrene was confirmed by trapping with 2,3-dimethyl-2-butene to form the aziridine and with oxygen to generate the nitrate ester. 2-Nitro substitution on the benzyl derivative had surprisingly little effect on the reaction course. For each compound examined, minor amounts of nitric oxide (NO), presumably produced by secondary photolysis of the nitrosamine, were observed. Time-resolved infrared experiments provided additional support for the above reaction pathways and confirmed that the nitrosamine is a primary photoproduct. We have also found that the relative contributions of the reaction pathways can be altered in certain derivatives. For example, when R' = 2,4-dinitrophenyl, the contribution of the nitrosamine/O-nitrene-forming pathway was diminished. Pharmacological implications of these results are discussed.

Mechanism of Photochemical O-Atom Exchange in Nitrosamines with Molecular Oxygen

“…63 The dimerization of nitrooxide A to hexaoxadiazocane C is reminiscent of the coupling of a carbonyl oxide yielding a dimeric benzophenone peroxide 64 and also nitrosooxide yielding a tetraoxadiazine. 27 Furthermore, the photocyclization of A and B is similar to that reported for the photocyclization of nitrosooxide to dioxaziridine, 35,42,65 where 18 O labeling also showed aryl dioxaziridines arise in the photooxidation of aryl azides (λ > 350 nm) using 18 O 2 gas by photocyclization of the aryl nitrosooxide. 40,41 In summary as described above, a photochemical process that transposes an 18 O label from molecular oxygen 18 O 2 was seen for nitrosamines 1 and 2, but not for 3 and 4.…”

Photochemistry of 1-(N,N-Diethylamino)diazen-1-ium-1,2-diolate: An Experimental and Computational Investigation

“…Anions with the X[N(O)NO] -(X ) O -, CR 3 , SO 3 -, and NR 2 ) functional group have been used increasingly as probes for studying the biology of nitric oxide (NO) and nitroxyl (NO -/ HNO) over the past decade, and have an expansive chemical history spanning two centuries. 1 1-(N,N-Dialkylamino)diazen-1-ium-1,2-diolates (X ) NR 2 ) are stable as solid salts, but release up to 2 mol of NO (plus 1 mol of amine) when dissolved in aqueous solution under physiologically relevant conditions.…”

Synthesis of Diazen‐1‐ium‐1,2‐diolates Monitored by the “NOtizer” Apparatus: Relationship between Formation Rates, Molecular Structure and the Release of Nitric Oxide

“…The apparatus was calibrated daily with 2.0 mL of a 0.1  KI/0.1  H 2 SO 4 solution in the chamber and an increasing amount of 50 µ NaNO 2 solution to produce nitric oxide by reduction. The nitrite solution was applied with an Eppendorf pipette (10,20,30,40 and 60 µL) to give 249, 493, 728, 952 and 1388 nM solutions of NO, respectively. The dissociation of the diazeniumdiolates was measured by injecting a 50 µ NONOate/0.01  NaOH solution (20 µL) into phosphate buffer (2.0 mL, pH 6.4) resulting in a 495 nM solution of NONOate.…”