Nitroso type Compounds

Nitroso-Type Compounds. Nitroso compounds (R—N=0) show reactivity as dienophiles in Diels-Alder reactions, giving heterocyclic rings. In Kibayashi s synthesis of fasicularin, for example, hydroxamic acid 180 was treated with tetrapropylammonium periodate in the presence of 9,10-dimethyl-anthracene to give transient acylnitroso compound 181, and the resultant Diels Alder product 182 was formed in 84% yield. In this particular example, the Diels-Alder adduct essentially protected the acyl nitroso unit, which was used in a subsequent reaction. 

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Primary amines. The nitrosation of primary amine type compounds yields small amounts of secondary amine type N-nitroso compound (14, 15, 16). The reaction mechanism is not well understood. 

Tertiary amines. Tertiary amine type compounds, react with nitrous acid to yield secondary-amine type N-nitroso compounds. The myth that tertiary amines do not nitrosate to yield N-nitroso compounds, is a remarkable feat of misinformation that has persisted for over 100 years (23, 24, 25). 

Free radicals are well known to add on activated olefins [241], Thus, in electrochemistry, the indirect formation of a free radical in solution may happen concomitantly by reaction on the mediator inside a solvent cage. Two examples follow. First is the indirect reduction of RX types compounds by the radical anion of a spin marker [242] such as a nitroso derivative. In this case the reaction is monoelectronic, since the nitroxyde radical is totally electroinactive (note that a nucleophilic action of the radical anion cannot be totally excluded (Scheme 46). 

Figure 9. Chemical structure of nitroso and triazine type compounds.

Some reference to the use of nitrous acid merits mention here. Primary aromatic amines yield diazonium compounds, which may be coupled with phenols to yield highly-coloured azo dyes (see Section IV,100,(iii)). Secondary aromatic amines afford nitroso compounds, which give Liebermann a nitroso reaction Section IV,100,(v). Tertiary aromatic amines, of the type of dimethylaniline, yield p-nitroso derivatives see Section IV,100,(vii). ... 

N Nitroso amine (Section 22 15) A compound of the type R2N—N=0 R may be alkyl or aryl groups which may be the same or different N Nitroso amines are formed by ni trosation of secondary amines... 

Retarders were originally arenecarboxylic acids. These acidic materials not only delay the onset of cross-linking but also slow the cross-linking reaction itself. The acidic retarders do not function weU in black-fiUed compounds because of the high pH of furnace blacks. Another type of retarder, A/-nitroso diphenylamine [86-30-6] was used for many years in black-fiUed compounds. This product disappeared when it was recognized that it trans-nitrosated volatile amines to give a several-fold increase in airborne nitrosamines. U.S. production peaked in 1974 at about 1.6 million kg. 

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

Formation of azo-type products might be troublesome. These by-products, arising from reduction of aromatic nitro compounds, usually are assumed to be derived from the coupling of intermediate nitroso and hydroxylamine compounds. The coupling problem is accentuated in reduction of nitroso compounds because of much higher concentrations. It can be alleviated by dropwise addition of the substrate to the hydrogenation and use of acidic media. 

The mechanisms of these reductions have been very little studied, though it is usually presumed that, at least with some reducing agents, nitroso compounds and hydroxylamines are intermediates. Both of these types of compounds give amines when exposed to most of these reducing agents (19-43), and hydroxylamines can be... 

If the concepts and facts presented in this paper are correct, a major kind of human cancer in many regions of the world, cancer of the stomach, is due to a type of nitroso compound, a nitrosoureido derivative, even though not a nitrosamine It is quite certain that the formation of such compounds can be blocked by vitamin C and vitamin E, as well as by some other substances such as gallates Thus, the primary prevention of cancer caused by nitroso compounds is readily accomplished through an adequate Intake of such harmless inhibitors with every meal from infancy onwards ... 

The process, once initiated, is self-sustaining and may become more accelerated with time because the atrophy and intestinal metaplasia are progressive lesions and lead to further loss of parietal cells and incrased bacterial colonization of the mucosa. The initial mutations transform gastric cells into mature intestinal-type cells. Further superimposed mutations transform metaplastic cells into progressively dysplastic cells and eventually into neoplastic cells. This is a process of loss of differentiation which implies a multihit phenomenon which could be explained on the basis of continued formation of minute amounts of nitroso compounds over many years. 

Type II nitrosamines have two reaction pathways. One pathway involves nucleophilic attack at the carbon of C=0 to generate a tetrahedral intermediate which decomposes to an active diazotate ion (R-N=N-0 ). The other pathway involves the nucleophililc attack on the nitrogen of the nitroso group resulting in denitrosation (Scheme 3.5). The nucleophile can be a biologically prevalent thiol, therefore type II compounds are often used as NO donors for the formation of S-nitrosothiols [67, 68]. 

In general, type II compounds show greater NO-releasing ability than type I N-nitrosamines. This can be explained by the electronic repulsion between the carbonyl oxygen and nitroso oxygen, or the attraction of the lone-pair electrons at nitrogen, by the carbonyl group both features weaken the N-NO bond. 

Due to the electron-demanding carbamoyl substructure on the nitroso hydrazine intermediates 129 the oxidative process that initiates the NO-release is much slower than with the active sydnonimine metabolites. The elimination of HNO from the nitroso intermediates and the subsequent oxidation to NO cannot be completely ruled out for this type of compounds. In vivo, an alternative, possibly thiol mediated route for the NO formation plays a role in the activity [147]. In this reaction the formation of nitrosothiols as unstable NO precursor intermediates is the most likely process. 

Rate constants for spin trapping of alkyl radicals measured by the procedures outlined here, are collected with other spin-trapping rate data in Table 5. It will be seen that most nitrone and nitroso traps scavenge reactive radicals of diverse types with rate constants generally in the range 10s-10 1 mol-1 s l. Of the nitroso-compounds, the nitroso-aromatics (except for the very crowded TBN) are particularly reactive, whilst MBN and DMPO are the most reactive nitrones. Much of the data for spin trapping by nitrones has been accumulated by Janzen and his colleagues, who have discussed in a short review how steric and electronic factors influence these reactions (Janzen et ai, 1978). 

Several force fields have been used in molecular mechanics calculations of amino, nitro and nitroso compounds. The most intensive work has been done with MM2 and, in recent years, also with MM3, probably due to the generally recognized high performance of these force fields and since they are the only ones which have undergone extensive specific parameterization for these systems, however, several other calculations are also found in the literature (see below). We therefore start with the MM2 and MM3 force fields where we briefly outline the specific form of the potential functions and discuss, in some detail, the parameterization procedure for the type of compounds discussed in this chapter. We then turn to several other force fields which have not undergone specific parameterization but were nevertheless used in the calculations (AMBER, Tripos, DREI-DING, UFF). We conclude with a brief comparison of the energetic performance of all force fields. 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

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