Denitrosation

The sodium carbonate may be omitted if it is desired to titrate the acid formed in the reaction The carbonate prevents denitrosation (observed in a few cases). 

Casado et al. (1986) assume that these isotope effects involve only the deprotonation rates (Ar3). It seems to the present author that a small isotope effect may also be present for the denitrosation rates (k 2). 

There is no reference to the formation of the ortho nitroso amine in the benzene series, indeed the formation and characterisation of ortho nitroso amines from any reaction has only been reported once or twice79. When the para position is blocked by a substituent, de-nitrosation so the secondary amine can occur80 a certain amount (which depends on the conditions) of denitrosation occurs also, concurrently with the rearrangement81, so that N-nitroso-N-methylaniline (XLVII) yields N-methylaniline (XLVIII) as well as the rearrangement product p-nitroso-N-methylaniline XLIX, viz. 

A second example is given in Eq. (10-12), which represents the denitrosation of A-methyl-Af-nitrosoanilines by acid.10 The Hammett plot shows upward curvature because the mechanism changes along the series. 

A Hammett plot (a) of the apparent first-order rate constants for semicarbazone formation at pH 3.9, where a change in the RCS occurs, and (b) of the denitrosation of A-methyl-A-nitrosoanilines, where the mechanism changes. Data are from Refs. 9 and 10. 

Sodium dodecyl sulfate and hydrogen dodecyl sulfate have been used as catalysts in the denitrosation iV-nitroso-iV-methyl-p-toluenesulfonamide [138]. The kinetics of condensation of benzidine and p-anisidine with p-dimethylamino-benzaldehyde was studied by spectrophotometry in the presence of micelles of sodium dodecyl sulfate, with the result that the surfactant increases the rate of reaction [188]. The kinetics of reversible complexation of Ni(II) and Fe(III) with oxalatopentaaminecobalt(III) has been investigated in aqueous micellar medium of sodium dodecyl sulfate. The reaction occurs exclusively on the micellar surface [189]. Vitamin E reacts rapidly with the peroxidized linoleic acid present in linoleic acid in micellar sodium dodecyl sulfate solutions, whereas no significant reaction occurs in ethanol solution [190]. 

The initial product is a salt of hydrazinesulfonic acid, which is converted to the hydrazine by acid treatment. Diazonium salts can also be reduced to arenes (14-24). N-Nitrosoamines can be denitrosated to secondary amines by a number of reducing agents, including H2 and a catalyst, BF3—THF—NaHC03, and NaBH4— TiCU, as well as by hydrolysis. ... 

The present data give us no indication of what the other pathways of DMN metabolism might be. Other pathways, including denitrosation and reduction of the NO group to the unsymmetrical hydrazine have been reported (27). 

Metabolism of NHEX- C in the rat results in dose dependent formation of C02> with 45% exhaled after a dose of 8 mg/kg NHEX but only 4% after 576 mg/kg (17). Similar results were obtained for NPYR and nitrosoheptamethyleneimine. At doses of 8-12 mg/kg NHEX, 33-37% of the radioactivity was excreted in the urine (17, 52). Urinary metabolites of NHEX were e-caprolactam, e-amino-caproic acid, and 6-aminocaprohydroxamic acid (52). The formation of 6-caprolactam is analogous to results with NPYR and NNN, in which 2-pyrrolidinone and norcotinine were observed as urinary metabolites. Caprolactam did not originate from hexamethylene-imine, a product of denitrosation. 

Scheme Concurrent acid catalysed denitrosation and deaunination...

N-nitrosamide and the solvent acidity, but generally denitrosation is more strongly acid-catalysed hence, it is a minor reaction ( <109 ) above pH 2 and the major pathway in concentrated acid ... 

This difference is exemplified by the variation of the pseudo first order rate coefficients (Rate = k [Substrate]) for the deamination and denitrosation of N-n-butyl -nitroso acetamide at 25 C with [HpSO ] shown in Figure 1 Denitrosation becomes the domin- ant pathway above 5M H SO. (9) but the crossover acidity i lower (ca.0 5M. H SO ) ror N-nitroso-2-pyrrolidone (10) ... 

The acid catalysed denitrosation of N-nitrosamides is subject to a substantial solvent deuterium isotope effect [k (H)/k (D)... 

Figure L Variation in the rates of denitrosation and deamination of S-n-butyl- H-nitrosoacetamide with [H SO ] at 25°C (9),...

In another study exposure of water containing NDEA to sunlight caused a raoid decrease in the NDEA concentration (to near zero after 16 h)2Q. Wolfe, et al. 2fi found Ji-nitrosoatrazine to be photolabile in natural water with both denitrosation and dealkylation being identified as decomposition pathways. 

Therefore, the N-nitroso derivative must be denitrosated to make the process economical as well as avoid high concentrations of the N-nitroso derivative in the product. The preferred method of nitration and denitrosation of... 

Sulfamate reduces nitrite to molecular nitrogen and serves as a denitrosating agent in the synthesis of pendimethalin (Diehl et al, 1979). 

Ross and Chiarello (1979) have described a method for denitrosation of nitrosamines, such as dlalkylnitrosamines e.g. N-nitrosodimetl laminer etc., and complex aryl-alkyl nitrosamines, e.g. N-nitroso-N-(l-ethylpropyl)-3,4-dimethyl-2,6-dinitroaniline. The products of nitration and amination containing nitrosamlne as a substantial impurity are treated with an aldehyde or ketone in the presence of strong acids such as hydrochloric or hydrobromic acid. Under pressurized conditions at 105-110% for cme to two hours, the nitrosamlne is destroyed. The desired product can be recovered after neutralization of the excess acid. The equation shows the denitrosation of pendimethalin ... 

Analytical Datay Showing the Degree of Denitrosation Achieved in the Above Reaction... 

Biggs and Williams (1976) have studied denitrosation over a wide range of acidities. They demonstrated that rate constants for denitrosation and rearrangements could be measured by limiting experimental conditions for N-alkyl-N-nitrosoanilines which is applicable to N-nitroso-dinitroaniline herbicides such as pendimethalin and butralin. 

Type II nitrosamines have two reaction pathways. One pathway involves nucleophilic attack at the carbon of C=0 to generate a tetrahedral intermediate which decomposes to an active diazotate ion (R-N=N-0 ). The other pathway involves the nucleophililc attack on the nitrogen of the nitroso group resulting in denitrosation (Scheme 3.5). The nucleophile can be a biologically prevalent thiol, therefore type II compounds are often used as NO donors for the formation of S-nitrosothiols [67, 68]. 

Intracellular and extracellular RSNO metabolism has been studied in LPS activated macrophages (Zhang and Hogg, 2003). This study showed that 0.02% of the NO produced in response to LPS, (detected as N02 ) was converted to cytosolic RSNOs and that all of the RSNOs detected were in the large molecular weight (>3K) protein fraction and were very stable to denitrosation (t1(f2 3h). These authors also showed that the molecular specie(s) responsible for S-nitrosation is freely diffusible and has to be transported to the cell surface before internal S-nitrosation could take place. 

The second activity, termed denitrosation (Eq. (15)), is catalyzed by the reduced form of the same active site thiols that are involved in the thiol-disulfide exchange activity of the enzyme (Zai et al, 1999 Ramachandran et al. 2001 Raturi and Mutus, 2004). In this process csPDI catalyzes the release of NO from RSNOs. 

Raturi, A., Mutus, B., Use of 2,3-diaminonapthalene for studying denitrosation activity of protein disulfide isomerase, Anal Biochem. 

Keefer LK, Anjo T, Wade D, et al. Concurrent generation of methylamine and nitrite during denitrosation of N-nitrosodimethylamine by rat liver microsomes. Cancer Res 1987 47(2) 447-452. 

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