Hydroxylamino group

Tiiazine A-oxides can be obtained by two general methods by direct oxidation of the parent 1,2,4-tiiazines with organic peracids, and by the formation of the A-oxide group of the 1,2,4-triazine ring by cyclization involving nitro, nitroso (isonitroso), or hydroxylamino groups. 

B. Synthesis of 1,2,4-Triazine 4-Oxides by Cyclization Involving Nitroso (Isonitroso) or Hydroxylamino Groups... 

It is known that 1,2,4-triazine 4-oxides, in contrast to 1,2,4-triazine 1- and 2-oxides, cannot be obtained by oxidation. Therefore, the only way to obtain 1,2,4-triazine containing the A -oxide group at position 4 of the heterocycle is to form the tiiazine ring by cyclization, starting from compounds bearing nitroso (isonitroso) or hydroxylamino groups. There are several ways to carry out such cyclizations. 

With D.F.P., the reaction was far more difficult and this led Wilson to combine the hydroxylamino group with a suitably placed N structure in the same molecule. Oximes will also restore activity of poisoned cholinesterase.8... 

Hydroxylamino groups differ from normal amino groups by their smaller 7i-donating power. Hydroxylaminoboranes, therefore, are stronger Lewis acids than aminoboranes, having a vacant boron p-orbital more easily available. The lack of reactivity of aminoboranes indicates that the Lewis acidity of the boranes plays an important role in the boration of iminoboranes. Again, iminoboranes seem to favor electrophilic attack. 

Aromatic nitro compounds were among the first organic compounds ever reduced. The nitro group is readily converted to a series of functions of various degrees of reduction very exceptionally to a nitroso group, more often to a hydroxylamino group and most frequently to the amino group. In addition azoxy, azo and hydrazo compounds are formed by combination of two molecules of the reduction intermediates (Scheme 58). 

Values of electrical effect substituent constants for oxime and hydroxylamino groups have been reported ° their values are set forth in Tables la-c. No value for the acid group, CO(NHOH), was available. We have estimated values for it they are given in Tables la-c. Also in Tables la-c are values for some other types of substituents either for purposes of comparison or because they were used in correlations in this work. 

Generally amino acid conjugation is a detoxication reaction. However, amino acid conjugation with hydroxylamino groups (N-hydroxy) can lead to the formation of reactive nitrenium ions, as already discussed with sulfate conjugation and acetylation. For example, the conjugation of serine with N-hydroxy-4-aminoquinoline-l-oxide (Fig. 4.40 for structure) leads to such a reactive nitrenium ion. This requires the enzyme serine-tRNA synthetase. 

In other cases, conjugation of an aromatic hydroxylamino group yields a positively charged nitrenium ion. Reactive intermediate metabolites and positively charged electrophilies can also be produced by reduction. For example, metals salts such as chromate can be reduced (to Cr3+) and nitro groups can be reduced to nitroso groups. 

N-Hydroxyindols (11) have been prepared in two ways,65 [Eqs. (24) and (25)]. Equation (25) is a variation in which the hydroxylamino group is oxidized to a nitroso group, which then adds to a C=C bond. In acidic solution the N-hydroxy group can be reductively removed. 

The mechanism of the reductive ring closure by formation of a nitrogen-nitrogen bond is often closely related to the mechanism of the formation of azoxy compounds. This has mostly been formulated as an attack of the nucleophilic hydroxylamino group on the positive center in the nitroso group, followed by loss of water. Inasmuch as the system ArNO + 2 e + 2 H + ArNHOH generally is electrochemically reversible, it is not unlikely... 

In acidic solution the reaction is different, and after workup (oxidation by air), 3-phenothiazinone (93) was isolated. It seems likely that the ring closure begins with a protonation of the hydroxylamino group, followed by loss of water and attack of the other hydroxylamino group on the electrophilic center of the C—N bond [Eq. (75)]. 

A ring closure may occur by reaction between a nitroso group and an amino group thus o-nitrobenzylamines (98) may be reduced to the hydrox-ylamine in an ammonia buffer and the hydroxylamino group oxidized to a nitroso group. If the amino group is primary or secondary, indazoles (99) are formed159 [Eq. (77)]. 

A reductive coupling is possible whenever two aromatically bonded nitro groups are in such a position that a 6- or 7-membered ring may be formed. The coupling occurs probably between a hydroxylamino group and an intermediate nitroso group with the formation of a cyclic azoxy derivative, a heterocyclic V-oxide. 

Reaction of halopyridazines with hydroxylamine to give hydroxyla-minopyridazine has been achieved only with activated compounds [79H(12)1157, 79JHC861], This has been ascribed to the low nucleo-philicity of hydroxylamine when compared to that of amines or hydrazines. A 3-hydroxylamino group reacted with bromoacetaldehyde at room temperature to give the first example of an imidazo[l,2-ft]pyridazine 1-oxide (8IT1787). 

Correlation of the half-wave potentials of meta- and para-substituted phenylarsonic acids with the Hammett substituent constants, cr, has been tried . The equation 1/2 = (0.053 0,010)o- — 0.705 V vs NHE (r = 0.9946) was obtained for a series of five compounds (unsubstituted, 4-OH, 4-NHj, 4-Me, 3-NH2-4-OH) studied in 0.02 M HCl, while under the same conditions the equation jy2 = 0.173(7 — 0.703 V vs NHE (r = 0.9991) was obtained for the second reduction of a series of three N02-substituted phenylarsonic acids using the a value for —NHOH for the reduced nitro group , i.e. apparently two different correlations exist. However, the possible protonation of the amino or hydroxylamino groups under the experimental conditions was not taken into account, and the validity of assigning the a value of the reduced substituent to the combined substituent/arsonic acid reduction taking place at the potential of the second wave was not discussed. It is therefore not surprising that the data cannot be described by a simple Hammett relation. For the simple para-substituted phenylarsonic acids a linear relation (equation 15) was found between the half-wave potential and the value of the arsonic acid. 

When a substituent is para to the hydroxylamino group, an ipso substitution may take place this may result in a loss of the substituent or a rearrangement. 

The hydroxylamino group may react further. A Gatterman reaction has, however, been observed only in the reduction of 2,3-dinitrotoluene. When a carboxyl group is neighbor to the hydroxylamino group, an isoxazolone may be formed this reaction has been used as an indication of which nitro group is most easily reduced in dinitrobenzoic acids [152]. 

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