Diazohydroxide intermediate

When the nitrosourethane, 4-(N-carbethoxy-N-nitrosamino)-butanal, was hydrolyzed at 37 , 2-hydroxytetrahydrofuran was also the major product isolated (40-50%). The latter was also formed when the nitrosourethane was allowed to react with aqueous base, under conditions known to convert nitrosourethanes to diazohydroxides (54). These results are consistent with the intermediacy of an oxocarbonium ion as shown in Figure 6, although direct attack of water on the diazohydroxide intermediate cannot be excluded. 

An arenediazonium ion 1 in aqueous alkaline solution is in equilibrium with the corresponding diazohydroxide 4 The latter can upon deprotonation react with diazonium ion 1, to give the so-called anhydride 5. An intermediate product 5 can decompose to a phenyl radical 6 and the phenyldiazoxy radical 7, and molecular nitrogen. Evidence for an intermediate diazoanhydride 5 came from crossover experiments " ... 

Despite these critical remarks, this discussion may be summarized by saying that the participation of the nitrosoamine (3.7), of its conjugate O-acid (3.8), of the (Z)-or (i -diazohydroxide (3.9), and of their conjugate acids (3.10) in the system of Scheme 3-36 remains more or less conjectural, but at least the nitrosoamine (3.7) does appear to be reasonable well documented as an intermediate on the pathway to the diazonium ion. 

The reversibility of aromatic diazotization in methanol may indicate that the intermediate corresponding to the diazohydroxide (3.9 in Scheme 3-36), i. e., the (Z)-or (is)-diazomethyl ether (Ar — N2 — OCH3), may be the cause of the reversibility. In contrast to the diazohydroxide this compound cannot be stabilized by deprotonation. It can be protonated and then dissociates into a diazonium ion and a methanol molecule. This reaction is relatively slow (Masoud and Ishak, 1988) and therefore the reverse reaction of the diazomethyl ether to the amine may be competitive. Similarly the reversibility of heteroaromatic amine diazotizations with a ring nitrogen in the a-position may be due to the stabilization of the intermediate (Z)-diazohydroxide, hydrogen-bonded to that ring nitrogen (Butler, 1975). However, this explanation is not yet supported by experimental data. 

The condition K2>KX has far-reaching consequences. Consider the diazonium ion during neutralization one hydroxide ion is taken up but, unlike the oxalate ion, it cannot rest after the first stage. The diazohydroxide formed must lose a proton immediately to yield the diazoate, a second hydroxide ion acting as proton acceptor. In other words, the diazohydroxide is not a stable intermediate and is not present in aqueous solution in appreciable concentration. It follows that the diazohydroxide... 

Each of the curves in Figure 5-3 exhibits two or three pH regions in which the slope of the logarithmic plot is approximately —1, with intermediate regions where the slope is small or zero. Lewis and Hanson (1967) showed that in the case of (E,)-4-nitrobenzenediazoate the portion of the curve with slope —1 at relatively high pH was consistent with the acidity constant K3 of the (E )-diazohydroxide determined either by titration or spectrophotometrically, the relevant results being (by... 

Jahelka et al. (1972 b) emphasize that Scheme 5-17 was derived assuming a steady state condition for all the intermediates of Scheme 5-14. The same authors (Jahelka et al., 1973a) found, however, in their investigation of the diazonium ion (Z)-diazoate equilibria (reactions 1 and 2) that the concentration of the intermediate (Z)-diazohydroxide may reach several percent, in one case even 25% (see Table 5-1). The very good fit of the calculated curves with the experimental data in Figure 5-3 is therefore rather surprising to the present author. 

The reaction with nitrite proceeds smoothly and with relatively high yields of the corresponding nitroarene (see Sec. 10.6). Obviously a major part of the driving force of this reaction is the formation of a stable, i. e., an energetically favorable, radical, nitrogen dioxide. With the hydroxide ion — a much stronger nucleophile than the nitrite ion — the reaction is expected to produce very unstable radicals, the hydroxy radical OH and the oxygen radical anion O, from the diazohydroxide (Ar - N2 — OH) and the diazoate (Ar-N20 ) respectively. Consequently, dediazoniation in alkaline aqueous solution does not follow the simple Scheme 8-41 with Yn = OH, but instead involves diazoanhydrides (Ar — N2 —O —N2 —Ar) as intermediates (see Sec. 8.8). 

Metabolic a-hydroxylation of NNN and NPy has been studied. This process may be the activation pathway for NNN and NPy since electrophilic diazohydroxides and carbonium ions are generated upon decomposition of the unstable intermediates a-hydroxyNPy,... 

The reaction (the Gomberg reaction or Gomberg-Bachmann-Hey reaction) probably involves the intermediate formation of the diazohydroxide, which... 

The synthesis of aryl azides in high yields and under mild conditions by the reaction of aromatic nitroso compounds with hydrazoic acid has been reported by Maffei and co-workers . Their results are summarized in Table 14. No intermediates have yet been isolated from this reaction, although Maffei suggested the intervention of a diazohydroxide. If the quantity of hydrazoic acid employed is less... 

The deamination of aliphatic amines The deamination of primary amines is the best known reaction involving aliphatic diazonium ions. The ions are probably produced within a hydroxide ion pair formed by dissociation of an intermediate diazohydroxide. Alcohols are characteristic products of the reaction, even in non-aqueous solvents for which stringent precautions are taken to remove any free water formed (Bailey and Burr, 1953). The partial racemization of the product from optically active amines rules out the operation of a concerted S i mechanism. 

As all nitrosoureas, this agent rapidly and spontaneously decomposes into two highly reactive intermediates chloroethyl diazohydroxide and organic isocyanate. This can result in a reaction that inactivates specific DNA repair enzymes. Semustine is cell cycle nonspecific. 

The nitrosoureas, being unstable in water, and presumably under physiological conditions, decompose into alkylating and carbamoylating chemical species. A scheme was proposed for the decomposition of carmustine (BCNU) (Fig. 4-7). The decomposition of the unstable intermediate oxazolidine leads to a vinyl diazohydroxide, yielding a vinyl... 

Extensive study has been made of the modes of aqueous decomposition of BCNU, at least in part for the purpose of elucidating its mechanism of antitumor activity (24-28). Montgomery and coworkers foimd that N2 was quantitatively evolved during aqueous decomposition of the drug and used nitrogen production as the measure of rate of reaction (24). Furthermore, all aqueous decomposition schemes proposed to date for BCNU place the N-nitroso group in unstable intermediates (e.g., diazohydroxides) from which N2 is promptly evolved (16,24-30). 

Fragmentation reactions which give rise to multiple bonding between nitrogen atoms are exemplified by decompositions of aromatic diazohydroxides in acidic media to give aryl cations, nitrogen and water. Such reactions generally occur in two steps and the intermediate diazonium ion is well characterised by its electrophilic properties. 

It is assumed that nitrous acid forms in situ under the Knoevenagel diazotizaiton condition, which then combines with aniline to give a diazohydroxide, which can decomposes to yield the phenyl radical. However, in the presence of a strong acid, the diazohydroxide is further protonated and converted into the corresponding diazonium salt which may undergo a heterolytical or homolytical decomposition to give radicals or a cation intermediate, as shown below. 

Diazotization of a primary amine takes place through a series of steps. In the presence of strong acid, nitrous acid dissociates to produc e NO ions. These ions then react with the nitrogen of the amine to form an unstable fV-nitrosoaminium ion as an intermediate. This intermediate then loses a proton to form an A/ nitrosoamine, which, in turn, tau-tomerizes to a diazohydroxide in a reaction that is similar to keto—enol tautomerization. Then, in the presence of acid, the diazohydroxide loses water to form the diazonium ion. 

The pyrolyses of JV-nitroso-A-acetylamines also probably generate ion pairs in the usual non-polar reaction media, e.g. />-cymene, for little rearrangement is reported Diazoalkanes, formed by elimination from diazohydroxides, are unlikely intermediates in nitrous deamination, for neither ethylamine nor isobutylamine gives labelled products when the reaction is conducted in deuterated media these observations also exclude 7r-complex intermediates -... 

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