Nitrosoarene reaction mechanism

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

Another example is the reaction of indoles with nitrosoarenes in the presence of acids. The redox potentials of the reactants cannot justify an outer-sphere ET process, thus the formation of the phenylaminoxyl detected for the reaction carried out in the ESR cavity, could be more likely justified by an inner-sphere ET mechanism95. In fact the reaction of quinoline N-oxide with primary alkyl Grignards for which an outer-sphere mechanism was earlier proposed, takes place through classical nucleophilic addition96. 

At 120 °C and 1 atm, AH =18 Kcal mol and AS = -30 cal mol K have been calculated [112]. In nonpolar solvents such as decane the reaction does not proceed. The deoxygenation of the nitro group to nitroso is considered to be the rate determining step of the reaction, since the subsequent carbonylation of the nitroso compounds to give the isocyanate derivative is about ten times faster than the one of the nitro compound in the presence of [Rh(CO)2Cl]2 as catalyst [114, 115], a reaction which is accelerated by M0CI5. The mechanism of this reactions is discussed in more detail in Chapter 6 we mention here that side-on rhodium nitrosoarene complexes were proposed as intermediates. However, which really are the coordination modes of the nitrosoarene to rhodium(I) in this system is still a question to be solved. As a matter of fact, the known arylnitroso complexes of mononuclear rhodium(I) complexes have a nitrogen-o-bonded nitroso group [116], and some of them can catalyse the carbonylation of nitrosobenzene to PhNCO[117]. 

Leach AG, Houk KN. Transition states and mechanisms of the hetero Diels-Alder reactions of hyponitrous acid, nitro-soalkanes, nitrosoarenes, and nitrosocarbonyl compounds. J. Org. Chem. 2001 66 5192-5200. 

A notable exception to the rule of thumb that the nitrosoarene compound is favored under oxidative conditions is the observation of arylhydroxylamine rather than nitrosoarene metabolite in microsomal oxidase studies of arylamine metabolism (43). In vitro studies of N-oxidation generally contain the biological reductant NADPH, which can, by a mechanism independent of cytochrome P-450 catalysis, reduce any nitroso product back to the hydroxylamine state. Our studies on CPX-catalyzed oxidation of arylamines by H2O2 did not require a reductant such as NADPH, and thus, may better reflect the actual enzymatic or equilibrium product of oxidative reactions, including microsomal oxidations. Microsomal oxidations in which substrates such as cumene hydroperoxide are used in place of O2/NADPH should yield the nitrosoarene rather than arylhydroxylamine metabolite. In the case of 4-chloroaniline, the nitroso metabolite rather than the hydroxylamine metabolite was produced however, the major product was the nitroaromatic compound, indicative of further oxidation (55). This raises the hypothetical question as to whether... 

The electrophilic properties of arylhydroxylamine and nitrosoarene compounds arise from very different bond-forming and bond-breaking reactions and lack a common electrophilic intermediate. The differences in electrophilic intermediates between arylhydroxylamine and nitrosoarene compounds are sufficient to exert a strong effect on the preference of target nucleophile. In turn, the arylhydroxylamine and nitrosoarene compounds are expected to produce somewhat different products, including protein binding by two chemically distinct electrophilic mechanisms. 

Figure 25. Proposed mechanism for the reaction of nitrosoarene compounds with sulfhydryl groups. (GIu-SH is reduced glutathione Glu-S-S-Glu is oxidized glutathione).

Figure 28. Modification of the nucleophile mechanism for the reaction of nitrosoarene compounds with thiamine-dependent enzymes. Structure A is the putative reaction intermediate at the enzyme active-site. B is active acetate when R=H.

Klehr, H., P. Eyer and W. Schafer. 1985. On the mechanism of reactions of nitrosoarenes with thiols. Biol. Chem. Hoppe-Seyler 366 755-760. 

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