Nitrosoarene

Nucleophilic displacement of the butoxy group in 2-butoxy-3//-azepine (1) by the use of excess secondary amine is preferred by some workers64 to the photolysis or thermolysis of aryl azides, or the deoxygenation of nitro- or nitrosoarenes in amine solution, as a preparative route to Ar,Ar-dialkyl-3//-azcpin-2-amines, e.g. 2,... 

N-Hydroxy arylamines readily form glucuronide conjugates, but in contrast to the N-hydroxy arylamides, these are N-glucuronides which are unreactive and stable at neutral pH. The N-glucuronides are readily transported to the lumens of the urinary bladder and intestine where they can be hydrolyzed to the free N-hydroxy arylamines by mildly acidic urine or by intestinal bacterial 3-glucuronidases (13,14). Non-enzymatic activation of N-hydroxy arylamines can occur in an acidic environment by protonation (15,16) of the N-hydroxy group (VIII) as well as by air oxidation (reviewed in 17) to a nitrosoarene (IX). 

Nitrosoarenes are readily formed by the oxidation of primary N-hydroxy arylamines and several mechanisms appear to be involved. These include 1) the metal-catalyzed oxidation/reduction to nitrosoarenes, azoxyarenes and arylamines (144) 2) the 02-dependent, metal-catalyzed oxidation to nitrosoarenes (145) 3) the 02-dependent, hemoglobin-mediated co-oxidation to nitrosoarenes and methe-moglobin (146) and 4) the 0 2-dependent conversion of N-hydroxy arylamines to nitrosoarenes, nitrosophenols and nitroarenes (147,148). Each of these processes can involve intermediate nitroxide radicals, superoxide anion radicals, hydrogen peroxide and hydroxyl radicals, all of which have been observed in model systems (149,151). Although these radicals are electrophilic and have been suggested to result in DNA damage (151,152), a causal relationship has not yet been established. Nitrosoarenes, on the other hand, are readily formed in in vitro metabolic incubations (2,153) and have been shown to react covalently with lipids (154), proteins (28,155) and GSH (17,156-159). Nitrosoarenes are also readily reduced to N-hydroxy arylamines by ascorbic acid (17,160) and by reduced pyridine nucleotides (9,161). 

Figure 7. Reaction Mechanism for Nitrosoarenes (IX). RSH, glutathione or cysteine.

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

Benzofurazans can be obtained by several methods (1) by dehydration of o-quinone dioxime (2) from o-substituted nitrosoarenes and (3) deoxygenation of benzofuroxans <1984CHEC(6)393, 1996CHEC-II(4)229>. For example, trihydroxyimino derivative 280 treated with sodium hypobromite, or when boiled in aqueous ammonia, affords the corresponding substituted tetrahydrobenzofurazan 281 (Equation 54) <2000CHE996>. 

Photolysis of symmetrical dialkyl diaryl tetrazenes affords N alkylanilino radicals. These could be trapped only with nitrosoarenes. Neither PBN nor the more reactive MBN gave detectable spin adducts (Cheng and Shine, 1974). 

What about jr-electron donor substituents on nitrosoarenes other than dimethylamino Pedley gives us the enthalpies of formation for three hydroxy derivatives the isomeric 4-nitroso-l-naphthol, 2-nitroso-l-naphthol and l-nitroso-2-naphthol, species 45-47 respectively. Of the three species, only the first cannot have an intramolecular hydrogen bond. By analogy to nitrophenols75 — there being no thermochemical data for the more related and hence relevant nitronaphthols—we expect that species 46 would be less stable than 45. After all, gaseous 2-nitrophenol is ca 20 kJ mol 1 less stable than its 4-isomer. We recall from the discussion of the isomeric naphthylamines that 1- and 2-naphthol are of almost identical stability. This suggests that species 46 and 47 should be of comparable stability. Both expectations are sorely violated by the literature results the enthalpies of formation of species 45, 46 and 47 increase in the order —20.3 4.9, —5.4 6.2 and 36.1 4.7 kJmol-1 respectively. If there is experimental error, where does the error lie ... 

Anilines are converted into nitrosoarenes ArNO by the action of hydrogen peroxide in the presence of [Mo(0)(02)2(H20) (HMPA)]224, whereas catalysis of the reaction by titanium silicate and zeolites results in the formation of azoxybenzenes ArN (0)=NAr225. Azo compounds ArN=NAr are formed in 42-99% yields by the phase-transfer assisted potassium permanganate oxidation of primary aromatic amines in aqueous benzene containing a little tetrabutylammonium bromide226. The reaction of arylamines with chromyl chloride gives solid adducts which, on hydrolysis, yield mixtures of azo compounds, p-benzoquinone and p-benzoquinone anils 234227. 

SCHEME 1. Main reaction pathways during interaction of nitrosoarenes with thiols (RA denotes electron acceptor substituent and RD electron donor... 

TABLE 1. Comparison of characteristic properties of N—S conjugates emerging during die reaction of nitrosoarenes with alkanethiols1... 

At constant pH, the parameter p is dependent on the electronic effects of the nitrosoarene substituent(s). Using only definite acceptor substituted nitrosoarenes, a Hammett correlation on the a scale was obtained25. Separate investigation of fc2RSH and fc2(rearr) for a wider selection of nitrosoarenes reacting with GSH revealed reasonable correlation with Hammett a constants only for fc2RSH (p = +1.4). However, Utrearr) was found to fit better on the Hammett a+ scale (p+ = —3.5)30 [for further discussion of Utrearr) see Section II.D.l.b]. 

Azo- and azoxyarenes have been repeatedly observed during reactions of nitrosoarenes with thiols5-7,11,29 33 35 36 38. The latter family presumably emerges from the interaction of the TV-hydroxy arylamine with unreacted nitrosoarene, a reaction proceeding even in neutral solutions2,6 58. The formation of azoarenes may be due to condensation of the end-product arylamine with still unreacted nitrosoarene59. 

The reaction of nitrosoarenes with alkanethiols may provide a new and simple synthetic route to iV-aryl-S-alkylsullinarnidcs which has not been mentioned hitherto62. Nitrosoarenes are frequently accessible by simple redox reactions of the commercially available arylamines or nitroarenes2,71. High yields of the desired sulfinamide may be achieved by adjusting stoichiometry, pH and solvent polarity. With aryl thiols, however, this method may not be applicable because of the very sluggish reaction (see Table 2). Whether such a synthetic route can be extended to alkylnitroso compounds remains to be established. 

According to this mechanistic conception, jr-donor substituted nitrosoarenes exhibit a strong correlation between sulfenamide and arylamine yield, respectively, and the thiol concentration employed38,56. In the case of nitrosobenzene and 4-chloronitrosobenzene, however, the 1-thioglycerol proportion (1 2 and 1 25, respectively) had virtually no effect on the sulfinamide/sulfenamide ratio at pH 6-938. As to our understanding, this effect lacks any reasonable explanation. 

Formation of ring-substituted arylamine thio ethers occurs also by proton-catalyzed thermal rearrangement of the corresponding sulfenamides73,82,83. This alternative pathway may not completely be excluded in thio ether formation from nitrosoarenes, but it seems unlikely since these thio ethers were produced at neutral pH and low temperatures68. The discovery of the fc -conjugate additionally favors the pathway of nucleophilic ring addition of thiolate to the sulfenamide cation. 

Hitherto, thio ether formation has clearly been proved only in the case of the ji-donor substituted 4-nitrosophenetol and the electron-rich l-methyl-2-nitrosoimidazole. The low yields of this adduct (about 2% at 1 1- and about 10% at 1 5-stoichiometry for 4-nitrosophenetol reacting with GSH56) may be the reason for its rare discovery. However, other nitrosoarenes should yield this family, too. Semiempirical molecular orbital calculations (MNDO) indicate a similar positive charge at the exposition of the N-(methylthiol-S -yl)-aniline cation and -4-anisole cation as well (Scheme 6). Furthermore, formation of l-(glutathion-S -yl)-2-naphthylamine was reported to occur in mixtures of 2-nitrosonaphthalene and GSH12. 

Formation of several colored products during reaction of nitrosoarenes with thiols has been repeatedly observed12,26,68. Two different orange-colored conjugates were found during HPLC separation of mixtures of 4-nitrosophenetol and GSH. The UV spectra were indicative of a quinoid structure, and further studies revealed these adducts to be a monocyclic and a bicyclic conjugate. In both cases the reactive quinoid structure gives rise to formation of secondary, stable end products. 

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