Agents nitrosating

Nitrosamines are formed whenever nitrosating agents come m contact with secondary amines Indeed more nitrosamines are probably synthesized within our body than enter it... 

Fluoroaromatics are produced on an industrial scale by diazotization of substituted anilines with sodium nitrite or other nitrosating agents in anhydrous hydrogen fluoride, followed by in situ decomposition (fluorodediazoniation) of the aryldiazonium fluoride (21). The decomposition temperature depends on the stabiHty of the diazonium fluoride (22,23). A significant development was the addition of pyridine (24), tertiary amines (25), and ammonium fluoride (or bifluoride) (26,27) to permit higher decomposition temperatures (>50° C) under atmospheric pressure with minimum hydrogen fluoride loss. 

Special Precautions. Use of sodium nitrite or other nitrosating agents in formulations containing nikanolamines could lead to formation of suspected cancer-causing nitrosamines. 

V-Nitrosodiphenylamine can act as a nitrosating agent for other amines with all the consequences thereof (see A/-Nitrosamines). 

The NO nitrosating agents present in the atmosphere are often due to air poUution. High surface area fillers such as carbon black absorb NO and Hberate it during the vulcanization process. Of course, this is the process where NO is most likely to be in contact with the various accelerators. 

V-Alkylpipera ines and PIP can react with nitrosating agents such as nitrogen oxides, nitrites or nitrous acid to form nitrosamine derivatives (61,62). Piper a2ine dihydrochloride [142-64-3] reacts with aqueous sodium nitrite and HCl to give the dinitrosamine that melts at 156—158°C (61). 

The behaviour of pyrazoles towards nitrosation is similar to their behaviour described above towards diazo coupling, i.e. aminopyrazoles and pyrazolones readily react with nitrosation agents, like alkyl nitrites (81FES1019), to afford stable nitroso derivatives. Some simple nitrosopyrazoles have been isolated, for example the blue-green 3,5-dimethyl-4-nitrosopyrazole, and many others have been proposed as reactive intermediates in the direct conversion of pyrazoles into diazonium or diazo derivatives (Scheme 25) (B-76MI40402). 

Af-Halogeno-, fV-nitroso- and hence fV-amino-azetidines have been prepared from azetidines by reaction with positive halogen reagents and nitrosating agents, respectively (Section 5.09.2.2.3). 

When solutions of sodium nitrite (NaN02) aie acidified, a number of species ar e formed that act as nitrosating agents. That is, they react as sources of nitrosyl cation, N=0 . For simplicity, organic chemists group all these species together and speak of the chemistry of one of them, nitrous acid, as a generalized precursor to nitrosyl cation. 

We learned in the preceding section that different reactions are observed when the various classes of alkylamines—primary, secondary, and tertiary—react with nitrosating agents. Although no useful chemistr-y attends the nitrosation of tertiar y alkylamines, electrophilic aromatic substitution by nitrosyl cation ( n Q ) takes place with A,A-dialkyl-arylfflnines. 

The reactive species for the transfer of the nitrosyl cation NO+ is not the nitrous acid 2 but rather N2O3 4 which is formed in weakly acidic solution. Other possible nitrosating agents are NOCl or H2N02 ", or even free NO+ in strong acidic solution. The initially formed N2O3 4 reacts with the free amine 1 ... 

Diaminobiphenyl (former name benzidine) can be easily bisdiazotized, but is not cleanly monodiazotized by reaction with one equivalent of a nitrosating agent. However, 4-aminobiphenyl-4,-diazonium ions are formed in a triazene equilibration of a 1 1 mixture of 4,4 -diaminobiphenyl with biphenyl-4,4 -bisdiazonium salts in aqueous HC1 (Tauber, 1894 see also Sec. 13.4). Methods for mono- and bisdiazotiza-tion of 1,4-diaminobenzene (/ -phenylenediamine) have been described by Saunders and Allen (1985, p. 29 see also Sec. 2.2). 

As the amines become more weakly basic, the normal method of diazotization becomes progressively more difficult. The equilibrium between amine and ammonium salt increasingly favors the former which, usually because of its poor solubility in water, is prevented from taking part in the reaction. Research into the mechanism of diazotization has demonstrated that the important step is the addition of the nitrosating agent to the base of the amine. Thus, the acidity for each diazotization should be so chosen that the equilibrium concentration of base corresponds to that of its saturated solution. This rule leads to the use of higer concentrations of aqueous mineral acid for weakly basic amines. 

The rate is no longer second-order with respect to nitrous acid, but first-order. Therefore, N203 cannot be the nitrosating reagent. The marked acid catalysis, as seen in the term h0, indicates that the new nitrosating agent is some species whose equilibrium concentration increases rapidly with increasing acidity. As shown in Scheme 3-8, this may be the nitrosoacidium ion (H20 —NO), but could also be the nitrosyl ion (NO+). 

Nevertheless, the reaction in region B has other unusual features, notably in the pattern of substituent effects for 4-substituents this is the reverse of that observed in region A. From these and other considerations, Ridd s group (Challis and Ridd, 1962 de Fabricio et al., 1966) concluded that the nitrosating agent attacks the pro-tonated amine and is loosely associated with the aromatic ring in the transition state. 

The kinetics in region B are therefore consistent with a mechanism characterized by two postulates, one of which is ambiguous (NO+ or H20 —NO as nitrosating agent) and the other (reactivity of the protonated aniline) is in contrast to general experience in electrophilic substitutions. 

In summary, it is now more likely that the solvated nitrosyl ion, not the nitroso-acidium ion, is the nitrosating agent in diazotizations. 

It is appropriate to add here some comments on diazotization in anhydrous carboxylic acids. They may be relevant for the diazotization of heteroaromatic amines carried out in acetic acid/propionic acid mixtures (Sec. 2.2). Extensive studies by Casado et al. (1983, 1984) showed that in nitrosation of secondary amines the nitrosyl ion, nitrosyl acetate, and dinitrogen trioxide are formed, and all three may act as nitrosating agents. The results do not, however, account for the considerable improvement that is claimed in the patent literature (Weaver and Shuttleworth, 1982) to result from the addition of carboxylic acids in the diazotization of heteroaromatic amines. 

Actually the evidence by no means requires this mechanism since there is no reason why the nitrosamine itself should not act as a primary nitrosating agent (thus allowing cross-nitrosation) and there was no rate data available to support the idea of specific catalysis by hydrochloric acid. 

No accurate rate measurements have yet been carried out, but qualitative experiments showed that the exchange was acid-catalysed so that it is likely that the protonated form of the nitrosamine (LIII) acts itself as a nitrosating agent. This would account for all the earlier cross-nitrosations that have been observed without necessitating the prior formation of nitrous acid, nitrosyl chloride or any other carrier of NO+. 

Table III shows that any of the higher oxidation states of nitrogen can serve as a nitrosating agent. To form a nitrosamine, all that need happen is for a nitrosating agent to encounter a nitrosatable substrate under favorable conditions, which might (but need not) involve acceleration of the reaction rate by one of the chemical or physical agents indicated in Table IV.

Table III. Nitrosating Agents Nitrogen Oxidation State Reference...

X"=N03") to yield N2O4. Both of these excellent nitrosating agents have been studied In considerable detail In recent years by Chains and coworkers (11). A closer look at the reactions of N2O4 with amines to form nitramlnes as well as nitrosamines can be found In Figure 2. Several examples are now known (10,... 

The results in Table II indicated that a nitrosating agent, produced in vivo, nitrosated morpholine or DMM in the homogenate, but did not nitrosate morpholine in vivo. To demonstrate more clearly the presence of this agent, we used the Iqbal method to prepare homogenate from mice exposed to NO but not gavaged... 

Table IV records a study of tissues in which the nitrosating agent occurred. Two mice were exposed to NO j killed with C02> and dissected to give the skin, liver, lungs, and remainder of the body ("carcass") Corresponding tissues of the 2 mice were combined and frozen in liquid N The entire tissue, or 5 g of the carcasses (total weight, 41 g) was homogenized, 10 mg...

It was possible that the nitrosating agent was N0 itself and that this disappears rapidly from the body after the NO exposure. To check this point, mice were exposed to 29 ppm NO2 for 4 h, air alone was passed into the chamber at 1.0 L/min for 10 min, and the mice were killed. The homogenate was mixed with 10 mg morpholine and worked up by the Iqbal method. The NMOR yield was 93 ng/g tissue (667o of the yield in Table II, exp. 

---