Amine with nitrosonium ions

Amines react with nitrous acid (formed by the reaction NaN02 + H HNO2) to give a variety of products. The nitrous acid isn t very stable, so generating it in place from sodium nitrite is necessary. (Sodium nitrite is a meat preservative and a color enhancer.) Under acidic conditions, nitrous acid dehydrates to produce the nitrosonium ion, NO. The NO ion is a weak electrophile that s resonance stabilized. (See Chapter 7.) Figure 13-22 illustrates the dehydration of nitrous acid. 

The nitrosonium ion (NO), generated in situ from sodium nitrite in the presence of hydrochloric acid at 0-5 °C, is also a weak electrophile and with tertiary amines, e.g. AyV-dimethylaniline, ring substitution occurs leading to the p-nitroso derivative (Expt 6.62). 

Most reactions with amines and nitrous add involve the nitrosonium ion. 

The reaction, called diazotization of an amine goes as follows Nitrous acid is pro-tonated by a strong acid to form the nitrosonium ion, Nitrosonium ion reacts with the primary amine to form AAnihosoammomum, an unstable compound., V-ni-trosoammonium deprotonates to form AAnitrosoamine. W-nitrosoamine tautomerizes to diazenol. In die presence of acid, diazenol dehydrates to diazonium... 

In an acidic solution, nitrous acid may protonate and lose water to give the nitroso-nium ion, +N=(). The nitrosonium ion appears to be the reactive intermediate in most reactions of amines with nitrous acid. 

Reaction with Primary Amines Formation of Diazonium Salts Primary amines react with nitrous acid, via the nitrosonium ion, to give diazonium cations of the form... 

R—N=N. This procedure is called diazotization of an amine. Diazonium salts are the most useful products obtained from the reactions of amines with nitrous acid. The mechanism for diazonium salt formation begins with a nucleophilic attack on the nitrosonium ion to form an A-nitrosoamine. 

Reaction with Secondary Amines Formation of IV-Nitrosoamines Secondary amines react with the nitrosonium ion to form secondary A-nitrosoamines, sometimes called nitrosamines. 

In the presence of acid, nitrous acid decomposes to " NO, the nitrosonium ion. This electrophile then goes on to react with the nucleophilic nitrogen atom of amines to form diazonium salts (RN2 Cr) from 1° amines and A -nitrosamines (R2NN=0) from 2° amines. 

The mechanism for this reaction consists of many steps. It begins with nucleophilic attack of the amine on the nitrosonium ion, and it can conceptually be divided into two parts formation of an A-nitrosamine, followed by loss of H2O, as shown in Mechanism 25.2. 

The preparation and reactions of diazonium salts. The reaction of aromatic amines with the nitrosonium ion (+NO), generated from nitrous acid (HN02), yields aryl diazonium salts, which can be converted (on loss of nitrogen) to a range of functional groups. 

Secondary aryl and alkyl amines react with a nitrosonium ion to form nitrosamines rather than diazonium ions. The mechanism of the reaction is similar to that for the reaction of a primary amine with a nitrosonium ion, except that the reaction stops at the ni-trosamine stage. The reaction stops because a secondary amine, unlike a primary amine, does not have the second proton that must be lost in order to generate the diazonium ion. 

The product formed when the nitrogen of a tertiary amine shares its lone pair with a nitrosonium ion caimot be stabilized by loss of a proton. A tertiary aryl amine, therefore, can undergo an electrophilic aromatic substitution reaction with a nitrosonium ion. The product of the reaction is primarily the para isomer because the bulky dialkyl-amino group blocks approach of the nitrosonium ion to the ortho position. 

Thus, unlike NO, HNO (not N—OH) can target cardiac sarcoplasmic ryanodine receptors to increase myocardial contractility, can interact directly with thiols and is resistant to both scavenging by superoxide (OJ) and tolerance development (Irvine et al. 2008). Nitrosonium (sometimes also termed nitrosyl cation) is very short lived in aqueous solution. Nitrosonium ions react with secondary amine to generate nitrosamines, many of which are eancer-inducing agents at very low doses (5.219). NO"" is formed in very small concentrations from nitrous acid in strong acid solution, when HNO2 reacts as a base ... 

In water, tertiary amines form quaternary ammonium compounds, e. g. with methyl halogenides. In aqueous solution, secondary (aliphatic and aromatic) amines react with nitrous acid HONO (namely the nitrosonium ion NO ) as already mentioned (reaction 5.217) to generate nitrosamines ... 

The nitrosonium ion is an extremely strong electrophile and is subject to attack by any amine that is present in solution. An equilibrium is established in which the concentration of nitrosonium ion is rather small. However, as the nitrosonium ion is formed, it can react with the amine that is present. The equihbrium then adjusts to produce more nitrosonium ion. The outcome of the reaction depends on whether the amine is primary or secondary. We will explore these possibdities separately, beginning with secondary amines. 

Primary amines react with a nitrosonium ion to yield a diazo-nium salt in a process called diazotization. 

This intermediate (the nitrosonium ion) is the intermediate we must focus on. Whenever we talk about an amine reacting with nitrous acid, we really mean to say that the amine is reacting with a nitrosonium ion (NO+). You might notice the similarity between this intermediate and the N02 intermediate (that we used in nitration reactions). Do not confuse these two intermediates. NO+ and N02 are different intermediates. In this section, we are only talking about the reactions of amines with the nitrosonium ion (NO ). 

As we said a few moments ago, nitrosonium ions cannot be stored in a bottle. Instead, we must make them in the presence of an amine. That way, as soon as the nitrosonium ion is formed, it will immediately react with the amine before it has a chance to do anything else. This is called an in situ preparation. 

So, now the question is what happens when an amine reacts with a nitrosonium ion Let s begin by exploring secondary amines (and then we will explore primary amines). 

Answer Our starting material is a primary amine. These reagents (sodium nitrite and HCI) are used to form nitrous acid, which then forms a nitrosonium ion. Primary amines react with a nitrosonium ion to give a diazonium salt. So, the product of this reaction is ... 

As mentioned in Section 7.16, many A-nitrosamines are potent carcinogens found in some food and tobacco smoke. Nitrosamines in food are formed in the same way they are formed in the laboratory reaction of a 2° amine with the nitrosonium ion, formed from nitrous acid (HNO2). Mechanism 25.3 is shown for the conversion of dimethylamine [(CH3)2NH] to A-nitrosodimeth-ylamine [(CH3)2NN=0]. 

Explain why a secondary amine forms a nitrosamine rather than a diazonium ion when it reacts with a nitrosonium ion. 

Nitrosating agents such as nitrous acid, dinitrogen trioxide, dinitrogen tetraox-ide, nitrosyl chloride, and alkyl nitrites are sources of NO (nitrosonium ion), which react with secondary amines to yield the corresponding A-nitrosamines. Similarly, secondary amides yield their corresponding A-nitrosoamides, ureas yield 7V-nitrosoureas, and carbamates, the 7V-nitrosocarbamates. 

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