C-Nitroso-compounds

Catalytic cleavage of the nitrogen-oxygen bond occurs very frequently as in reduction of nitro compounds, oximes, and various heterocyclics these reactions are discussed in separate chapters. Considered here are N-oxides, hydroxylamincs, and N- and C-nitroso compounds. 

C-Nitroso compounds with an a-hydrogen atom rearrange readily to the corresponding oxime (/7y) and perhaps to the unsaturated hydroxylamine 145). Reduction of these is discussed in the chapter on oximes. 

Ring nitrosation with nitrous acid is normally carried out only with active substrates such as amines and phenols. However, primary aromatic amines give diazonium ions (12-47) when treated with nitrous acid, " and secondary amines tend to give N-nitroso rather than C-nitroso compounds (12-49) hence this reaction is normally limited to phenols and tertiary aromatic amines. Nevertheless secondary aromatic amines can be C-nitrosated in two ways. The N-nitroso compound first obtained can be isomerized to a C-nitroso compound (11-32), or it can be treated with another mole of nitrous acid to give an N,C-dinitroso compound. Also, a successful nitrosation of anisole has been reported, where the solvent was CF3COOH—CH2CI2. " ... 

Carbons adjacent to a Z group (as defined on p. 548) can be nitrosated with nitrous acid or alkyl nitrites. The initial product is the C-nitroso compound, but these are stable only when there is no tautomerizable hydrogen. When there is, the product is the more stable oxime. The situation is analogous to that with azo compounds and hydrazones (12-7). The mechanism is similar to that in 12-7 R—H —> R + N=0 — R—N=0. The attacking species is either NO or a carrier of it. When the substrate is a simple ketone, the mechanism goes through the enol (as in halogenation 12-4) ... 

Tertiary aliphatic - aromatic amines, unlike those of the aliphatic series, react with nitrous acid with the formation of C-nitroso compounds the nitroso group enters almost exclusively in the para position if available, otherwise in the ortho position. Thus dimethylaniline yields -nitrosodimethylaniline ... 

R3N—N=0, but this then readily undergoes C—N fission to yield relatively complex products. With aromatic tertiary amines, ArNR2, nitrosation can take place not on N but at the activated p-position of the nucleus (cf. p. 137) to yield a C-nitroso compound ... 

N-Hydroxy-N-nitrosamines with an aliphatic group at O2 produce a compound stable to aqueous acid and base (Fig. 3.4, 29) [158], whereas all other N-hydroxy-N-nitrosamines are susceptible to hydrolysis and appropriate 02-derivatives also render these materials vulnerable. The hydrolysis endpoint is the formation of nitroxyl (HNO) [which dimerizes to form nitrous oxide (N20)] and a C-nitroso compound. These products are formed from aryl [159] and alkyl bound unsubstituted diazenium-diolates as well as Oralkylated derivatives [160]. Studies of the solvolysis of Oi-alkyl derivatives are complicated by their tendency to decompose via competing radical pathways [161], but the Oi-benzyl derivatives are unique in that they hydrolyze back to the original synthetic precursors (Scheme 3.14) [162]. 

The N-diazeniumdiolates are quite photosensitive. Studies of various 02-substi-tuted compounds, both alkyl and aryl, revealed a primary photochemical reaction involving cleavage of the N=N bond to yield a nitrosoamine and an O-substituted nitrene which rearranges to a C-nitroso compound (Scheme 3.31), the latter is often isolated as the oxime [224]. 

C-Nitroso compounds, oximes, N-hydroxyguanidines and N-hydroxyureas each contain an N-O bond and release nitric oxide (NO) or one of its redox forms under some conditions. The nitrogen atom of a C-nitroso compound formally exists in the +1 oxidation state, the same oxidation state as nitroxyl (HNO), the one-electron reduced form of N O. The nitrogen atoms of oximes, N-hydroxyguanidines, and N-hydroxyureas each formally exist in the -1 oxidation state, the same oxidation state as hydroxylamine. Consequently, the direct formation of NO (formal oxidation state = +2) from any of these species requires oxidation, one electron for a C-nitroso compound and three electrons for an oxime, N-hydroxyguanidine or N-hydroxyurea. This chapter summarizes the syntheses and properties, NO-releasing mechanisms and the known structure-activity relationships of these compounds. 

Alkyl and aryl C-nitroso compounds contain a nitroso group (-N=0) directly attached to an aliphatic or aromatic carbon. As compounds with a nitroso group attached to a primary or secondary carbon exist primarily as the oxime tautomer, the stable examples of C-nitroso compounds contain nitroso groups attached to tertiary carbons, such as 2-methyl-2-nitroso propane (1, Fig. 7.1) or nitroso groups attached to carbons bearing an electron-withdrawing group (-CN, -N02, -COR, -Cl, -OAc, Fig. 7.1). Oxidation of alkyl and aryl hydroxylamines provides the most direct route to alkyl and... 

Scheme 7.1 Thermolysis or photolysis of C-nitroso compounds to nitric oxide.

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

C-Nitroso Compounds, Oximes, N-Hydroxy guanidines and N-Hydroxyureas... 

Despite these interesting diversions, the vast majority of reports of investigations or applications of the spin-trapping technique depend on the use of C-nitroso-compounds or of nitrones the remainder of this review will be concerned exclusively with these two classes of scavenger. 

The pre-eminent advantage of C-nitroso-compounds as spin traps is that in the spin adduct the scavenged radical is directly attached to the nitroxide nitrogen. Consequently, the esr spectrum of the spin adduct is likely to reveal splittings from magnetic nuclei in the trapped radical, and these will greatly facilitate its identification. A simple example is presented in Fig. 2, which shows the spectrum of the spin adduct of the methyl radical with 2-methyl-2-nitroso-... 

Selected electron spin resonance data for spin adducts of C-nitroso-compounds (see also Table l)0 ... 

A very early indication that C-nitroso-compounds are particularly susceptible to radical attack was the methyl affinity value of 105 determined for nitrosobenzene (Heilman el al., 1957). This figure reflects the reactivity of nitrosobenzene, relative to that of benzene, towards attack by methyl radicals. It was apparently several years before this reactivity was linked with nitroxide formation... 

PE spectroscopic studies of C-nitroso compounds have sometimes been hampered by these properties, but also the dimer-monomer transformation has been studied by this technique125,126 (vide infra). 

The Hel PE spectrum of nitrosomethane (Figure 13) was first studied by Bergmann and Bock125,127. This compound as well as several other aliphatic and aromatic C-nitroso compounds were investigated by Pfab and coworkers126,128, however several of them were dimers. 

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