Nitroxides from nitrones

Oxidation of organonitrogen compounds is an important process from both industrial and synthetic viewpoints . N-oxides are obtained by oxidation of tertiary amines (equation 52), which in some cases may undergo further reactions like Cope elimination and Meisenheimer rearrangement . The oxygenation products of secondary amines are generally hydroxylamines, nitroxides and nitrones (equation 53), while oxidation of primary amines usually afforded oxime, nitro, nitroso derivatives and azo and azoxy compounds through coupling, as shown in Scheme 17. Product composition depends on the oxidant, catalyst and reaction conditions employed. 

Di(octadecyl)hydroxylamine (18) (Seltzer et al., 1989 PospiSil and Nespurek, 1997) was recently introduced commercially for the stabilization of PO, PP in particular. 18 is a hydrolysis-resistant processing stabilizer used in combination with aromatic phosphites, and a long-term heat stabilizer used in combination with suitable HAS. Di-alkylhydroxylamine is considered as scavenger of radicals POO" and P. The latter are trapped by nitroxide or nitrone, arising from the parent hydroxylamine (Eq. 3-7). 

Reactive free radicals also react with the nitrogen of nitroso groups, forming a nitroxide one atom closer to the trapped radical than is the case with nitrone spin traps. This results in ESR spectra containing more chemical structural information. While nitroso spin traps provide radical identification, the resultant adducts are often less stable than those derived from nitrone traps. In particular, nitroso traps are unreliable for oxygen-centered radicals even in vitro. 

Nitrones arc generally more stable than nitroso-compounds and arc therefore easier to handle. However, the nitroxides formed by reaction with nitrones [e.g. phenyl /-butyl nitrone (109)]483 484 have the radical center one carbon removed from the trapped radical (Scheme 3.86). The LPR spectra are therefore less sensitive to the nature of that radical and there is greater difficulty in resolving and assigning signals. Nitrones are generally less efficient traps than nitroso-compounds.476... 

Recently, the use of flash vacuum pyrolysis, at 420°C and at pressure less than 0.5 mm Hg has been described for the synthesis of isoindolyl nitrone 1,1,3-tri-methylisoindole A-oxide (TMINO) from isoindoline nitroxide 1,1,3,3-tetra-methylisoindolin-2-yloxy (TMIO), with yields up to 73% (Scheme 2.71) (354). 

The prime drawback with the nitrone traps, is the relative paucity of information immediately available from the spectra of the derived spin adducts. For example, with few exceptions the spin adducts of PBN [7] give six-line spectra with resolved splittings only from nitrogen and from the / proton. Identification of spin adducts must then be by careful comparison of the magnitude of the hyperfine splittings with those found for reference nitroxides... 

Skladanowski, A., and Konopa, J., 1993, Adriamycin and daunomycin induce programmed ceU death (apoptosis) in tumor ceUs. Biochem. Pharmacol. 46 375-382 Slater, A.F.G., Nobel, C.S.L, Maelaro, E., Bustamante, J., Kimland, M., and Orrenius, S., 1995, Nitrone spin traps and a nitroxide antioxidant inhibit a common pathway in thymocyte apoptosis. Biochem. J. 306 771-778 Snyder, R., Jowa, L., Witz, G., Kalf, G., and Rushmore, T., 1987, Formation ofreactive metabolites from benzene. Arch. Toxicol. 60 61-64. 

H. G. Aurich, in E. Breuer, H. G. Aurich and A. Nielsen, Nitrones, Nitronates and Nitroxides, updates from The Chemistry of Eunctional Groups (Eds.), S. Patai and Z. Rappoport, Whey, Chichester, 1989, p. 313. 

Under photo-stimulation, isoindolyloxyl radical (5) abstracts primary, secondary, or tertiary hydrogens from unactivated hydrocarbons including cyclohexane, isobutane, or n-butane (Scheme l).23 The nitroxide (5) traps the resultant carbon-centred radical (R ) and so afford the A -aI koxyisoindo les (6). Blank photolysis experiments with no added hydrocarbon have shown some unprecedented / -fragmentation of (5) to afford the nitrone (7). A number of C60 nitroxide derivatives have been synthesized and characterized by ESR spectroscopy which show features common to nitroxide radicals.24 Reaction of nitroxide and thionitroxide radicals with thiyl radicals have been observed, from which sulfinyl, sulfonyl, and sulfonyloxy radicals were generated.25 The diisopropyl nitroxide radical was generated in the reaction of lithium diisopropylamide with a-fluoroacetate esters.26... 

Further possibilities for nonenzymatic nitrone formation include the disproportionation of nitroxides in cases where the nitroxyl functionality is attached to an a-carbon bearing at least one hydrogen142 (equation 14), or the rearrangement of certain N-hydroxy compounds to the thermodynamically more stable tautomeric forms, as has been observed for the formation of a-aminonitrone from N--hydroxy-7V-methylbenzamidine50 (equation 15). 

Spin traps come in basically two types nitroso compounds and nitrone compounds. Reactive free radicals react with the carbon of the nitrone functional group to form a radical adduct that always has a nitroxide group, which is an unusually stable type of free radical. Nitrones are the most useful spin traps for the in vivo detection of free radical metabolites because of the stability of the resulting radical adduct. However, identification of the parent radicals can be difficult because adducts derived from different radicals often have very similar EPR spectra. A comprehensive review of this area through 1992 has recently been published [48]. 

Fig. 3.7. First derivative liquid-phase ESR spectra for nitroxide radicals formed by the spin-trapping method, (a) the CC13 adduct of PBN, showing hyperfine coupling to the 14N and H of the parent nitrone (b) the same species formed from l1-CClj radicals, showing the extra large doublet splitting from l3C (The /Mines are from an extraneous radical species.) (c) the hydroxyl radical adduct of DMPO, showing the characteristic 1 2 2 1 quartet, generated because of the fortuitous equality of the 1H and l4N splittings.

For such short-lived radicals, the technique of spin trapping may be employed (Janzen, 1980). This technique involves the addition of the radical (R ) to an organic diamagnetic nitrone or nitroso compound to form a longer lived nitroxide free radical. The structure of the parent free radical may then be determined from the hyperfine coupling of the ESR spectrum of the resultant spin adduct. Nitrones are very reactive and their adducts are stable, even though they do not provide much structural information. On the other hand, nitroso adducts have unique ESR spectra but they are photolytically unstable. 

Nitroxide 56 and analogous nitroxides generated from 4,4 -disubstituted DPA, PNA, DHQ or DHI should be categorized as the primary ones. ESR signals of NO observed in flex-cracked polymers may also arise from secondary nitroxides formed after R trapping by nitrones [4,73] (see Sect. 3.1.1.3, Scheme 11). These nitroxides are most probably those detected as the transformation species of PD. 

Nitroxides derived from amines having one hydrogen atom on a-carbon atom to nitrogen oxidize with ROO to nitrones [111] and/or disproportionate easily into the respective hydroxylamine and nitrone [112]. The cis and trans nitroxides derived from 18 differ in their disproportionation rates. The disproportionation proceeds via an intermediately formed dimer ... 

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