Amines, heteroaromatic

Compounds with a high HOMO and LUMO (Figure 5.5c) tend to be stable to selfreaction but are chemically reactive as Lewis bases and nucleophiles. The higher the HOMO, the more reactive. Carbanions, with HOMO near a, are the most powerful bases and nucleophiles, followed by amides and alkoxides. The neutral nitrogen (amines, heteroaromatics) and oxygen bases (water, alcohols, ethers, and carbonyls) will only react with relatively strong Lewis acids. Extensive tabulations of gas-phase basicities or proton affinities (i.e., —AG° of protonation) exist [109, 110]. These will be discussed in subsequent chapters. 

Amine Ar-imines are derived formally from tertiary amines by replacing the free pair of electrons by an imino group. Aliphatic, aromatic, or heteroaromatic compounds are obtained according to the nature of the amine. Heteroaromatic JV-imines are derived from heterocyclic compounds containing an azomethine nitrogen atom in the molecule. 

The vast majority of ILs are usually prepared by simple N- or T-alkylation of amines, heteroaromatics, and phosphines, often employing alkyl halides or alkyl sulfonates as alkylating agents, followed by association with metal halides or anion metathesis (Scheme 1). 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

This scheme eliminates the process of converting bis(etherimide)s to bis(ether anhydride)s. When polyetherimides are fusible the polymerization is performed in the melt, allowing the monamine to distill off. It is advantageous if the amino groups of diamines are more basic or nucleophilic than the by-product monoamine. Bisimides derived from heteroaromatic amines such as 2-arninopyridine are readily exchanged by common aromatic diamines (68,69). High molecular weight polyetherimides have been synthesized from various N,lSf -bis(heteroaryl)bis(etherimide)s. 

Basic Red 22 (134), which contains 1 part ia 7 of the yellowish red 1,4-dimethyl isomer, Basic Red 29 (135), and Basic Yellow 25 (136) are all examples of delocalized cationic azo dyes. Dyes of this type can also be synthesized by Hbnig s oxidative coupling reaction of heteroaromatic hydrazones with tertiary aromatic amines. 

The classical structures of pyrrole, furan and thiophene (31) suggest that these compounds might show chemical reactions similar to those of amines, ethers and thioethers (32) respectively. On this basis, the initial attack of the electrophile would be expected to take place at the heteroatom and lead to products such as quaternary ammonium and oxonium salts, sulfoxides and sulfones. Products of this type from the heteroaromatic compounds under consideration are relatively rare. 

Autocatalysis may arise when the nucleophilic atom of the reagent is bound to a hydrogen atom which is eventually eliminated during the reaction. This occurs with neutral reagents such as primary or secondary amines, thiols, and alcohols. If the displaced group (usually an anion) is a sufficiently weak base, the proton is effectively transferred to any basic reactant. Hence, the best known examples of autocatalysis involve chloro-A-heteroaromatic compounds as the substrates. 

Hydrazides of vicinal acetylene-substituted derivatives of benzoic and azole carboxylic acids are important intermediate compounds because they can be used for cyclization via both a- and /3-carbon atoms of a multiple bond involving both amine and amide nitrogen atoms (Scheme 131). Besides, the hydrazides of aromatic and heteroaromatic acids are convenient substrates for testing the proposed easy formation of a five-membered ring condensed with a benzene nucleus and the six-membered one condensed with five-membered azoles. 

The reactions of 4-alkoxybut-3-en-2-ones with primary aromatic amines and diamines of the aromatic and heteroaromatic series follow analogous schemes. 

Aromatic diazonium compounds became industrially very important after Griess (1866a) discovered in 1861/62 the azo coupling reaction, by which the first azo dye was made by C. A. Martius in 1865 (see review by Smith, 1907). This is still the most important industrial reaction of diazo compounds. Hantzsch and Traumann (1888) discovered that a heteroaromatic amine, namely 2-aminothiazole, can also be diazotized. Heteroaromatic diazonium compounds were, however, only used for azo dyes much later, to a small extent in the 1930 s, but intensively since the 1950 s (see Zollinger, 1991, Ch. 7). 

The diazotization of heteroaromatic amines is a ticklish procedure. In spite of the great increase in interest for disperse dyes based on heterocyclic diazo components,... 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

In certain cases where the heteroaromatic amine is insufficiently soluble in aqueous acid, it can be dissolved in the minimum volume of an organic solvent miscible with water. Dilute mineral acid and a solution of sodium nitrite are then added. An example is the diazotization of 2-phenyl-3-amino-4-acetyl-5-methyl-pyrrole (Dattolo et al., 1983). 

We mention Williams work briefly here because it may also explain Blangey s observations strongly basic primary amines unequivocally form 7V-nitrosoanilinium ions in strongly acidic media. In contrast to the rate-limiting deprotonations of the less basic aromatic and heteroaromatic nitrosoamine cations discussed in this section, the TV-nitroso cation of a strongly basic amine deprotonates extremely slowly. Therefore, the nitroso rearrangement, the Fischer-Hepp reaction, competes effectively with the 7V-deprotonation. 

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. 

In principle, the intermediates obtained under these conditions could have the structure of a nitrosoamine such as 3.12, but they could also be one of the isomers, namely a (Z)- or (ii)-nitrosoimine (3.14 or 3.15, respectively), or a (Z)- or (ii)-diazo-hydroxide (3.16 or 3.17, respectively). Analogous isomers exist, of course, for other nitrosation products of heteroaromatic amines. 

In the context of the stability of the nitrosoamine intermediate in the diazotization of heteroaromatic amines relative to that in the case of aromatic amines, the reversibility of diazotization has to be considered. To the best of our knowledge the reverse reaction of a diazotization of an aromatic amine has never been observed in acidic solutions. This fact is the basis of the well-known method for the quantitative analysis of aromatic amines by titration with a calibrated solution of sodium nitrite (see Sec. 3.3). With heteroaromatic amines, however, it has been reported several times that, when using amine and sodium nitrite in the stoichiometric ratio 1 1, after completion of the reaction nitrous acid can still be detected with Kl-starch paper,... 

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