Hydroxylamines amine oxidation

Primary amino groups are oxidized stepwise by ozone to hydroxylamine, nitroso, and nitro (54,58) tertiary amines are oxidized to amine oxides. 

Rearrangement, Aliphatic amine oxides without an ahphatic hydrogen atom P to the nitrogen undergo Meisenheimer s rearrangement when heated to give trisubstituted hydroxylamines. 

Elimination. Ahphatic amine oxides having an ahphatic hydrogen P to the nitrogen form olefins and diaLkyl hydroxylamines when heated. This reaction is known as the Cope elimination (17)... 

Amine oxides 2, which can be prepared by oxidation of amines 1, react upon heating to yield an olefin 3 and a hydroxylamine 4. This reaction is called the Cope elimination reaction,and as a synthetic method is a valuable alternative to the Hofmann degradation reaction of quaternary ammonium salts. 

Aromatic nitro and nitroso compounds are easily reduced at carbon and mercury electrodes. Other nitro compounds such as nitrate esters, nitramines, and nitrosamines are also typically easily reduced. The complete reduction of a nitro compound consists of three two-electron steps (nitro-nitroso-hydroxylamine-amine). Since most organic oxidations are only two-electron processes, higher sensitivity is typically found for nitro compounds. Several LCEC based determination of nitro compounds have been reported... 

The cycloaddition, reduction and oxidation reactions emanating from a,/J-unsatu-rated nitroalkenes provide easy access to a vast array of functionalities that include nitroalkanes, N-substituted hydroxylamines, amines, ketones, oximes, and a-substi-tuted oximes and ketones [73-75], Consequently, there are numerous possibilities of using these in situ generated nitroalkenes for the preparation of valuable building blocks and synthetic precursors. 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

Preparation of hydroxylamines through oxidation of an amino group is an attractive approach since a variety of primary and secondary amines are commercially available, including compounds with high enantiomeric purity. A number of reagents have been suggested for the oxidation. However, yields are variable and sometimes are difficult to predict, since primary hydroxylamines can undergo further oxidation into nitroso and nitro compounds. The overoxidation is less a problem for A,iV-disubstituted hydroxylamines... 

Tertiary Amines to Amine Oxides and Hydroxylamines to Nitrones... 

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

Figure 34 Oxidative reactions of amines. Formation of N-oxides from oxidation of tertiary amines and formation of hydroxylamines from oxidation of primary and secondary amines.

Cyclodextrin ketones have been used as powerful catalysts of amine oxidation in the presence of hydrogen peroxide as the stoichiometric oxidant. This oxidation follows Michaelis-Menten kinetics and depending on the substrate the oxidation rate is increased up to 1100-fold. It has been proposed that hydrogen peroxide reacts with the ketone to form a hydroperoxide adduct and this adduct is responsible for oxidizing the amine, bound in the cavity, to the hydroxylamine.189... 

Secondary amines are easily oxidized to hydroxylamines. Side products are often formed, however, and the yields may be low. The mechanisms of amine oxidations are not well characterized, partly because many reaction paths (especially those involving free radicals) are available. 

A variation of the Hofmann elimination, where a tertiary amine oxide eliminates to an alkene with a hydroxylamine serving as the leaving group, (p. 907)... 

Microsomes contain, in addition to the two cytochrome reductases just discussed, a flavoprotein which catalyzes the mixed function oxidation of secondary and tertiary amines to the hydroxylamines and amine oxides, respectively (333, 334). This flavoprotein, which contains about 2 moles of phospholipid and 1 mole of FAD per 70,000 g of protein, is specific for NADPH (333, 334) The enzyme is also able to catalyze the further oxidation of the hydroxylamines to nitrones (336). The reactions... 

Hydroxylamin N-Ethyl-N-tetrahy-drofurfuryl- Elba, 179 (Amin-Oxid.)... 

Ethan l-Acetamino-l-(4-methyl-phenyl)-2-nitro- E16d, 162 (En + NOf + R-CN) Hydroxylamin l-(4-Nitro-phenoxy)-E16a, 306 (Amin-oxid-Umlager.) Isoquinolin l-Hydroxyamino-5,6-methylendioxy-2-methyl-l, 2,3,4-tetrahydro- E16a, 13 (OH - NH-OH)... 

The thermal rearrangement of tertiary amine oxides, the Meisenheimer rearrangement, generates O, A,A-trisubstituted hydroxylamines. 

---