Ammonium salts reaction with amide bases

In an interesting catalysed conversion of trichloroethene by secondary amines into aminoacetamides, the initial steps are thought to involve the p-elimination of HC1 to produce dichloroethyne (Scheme 9.1), which reacts with the secondary amine under the wet conditions to produce the amide [35] the reaction does not work with N-alkylanilines. Such a mechanism is realistic, as it is well known [36] that trichloroethene is converted into the inflammable and explosive dichloroethyne by bases, and quaternary ammonium salts catalyse the formation of the alkyne when trichloroethene is reacted with oxiranes [37]. Chloroethynes have also been obtained by the catalysed reaction of terminal ethynes with carbon tetrachloride under basic conditions [38]. 

Correspondingly, metal amides in liquid ammonia have a basic character. The reaction of ammonium salt with metal amide in liquid ammonia is analogous to the neutralization of acid and base in water. The heats of neutralization in ammonia are even larger than in water. The process of hydrolysis corresponds to ammonolysis in ammonia. This results in ammonobasic compounds, for example, in the infusible precipitate HgNH2Cl from HgCl2. 

It is well known that halomethyleneiminium salts, often prepared in situ (see Section 2.1.2.2) react with ammonium salts, primary amines, secondary amides, urea and IV-substituted ureas to afrbrd amidinium salts, from which the free amidines can be obtained by addition of bases. > 4 Some recent results are given below. Dimethylformamide chloride and other 7V,iV-disubstituted formamide chlorides were reacted with acetanilides, chloroacetanilides, 6-aminopenam derivatives, 2-aminopyrimidine, 4-aminouracil, 2-amino-4-chloropyridazine, 2-aminothiazole, 2-aminobenzothiazole and thiobenzamides to give the amidines via the amidinium salts. In the reaction of MA -disubstituted formamide chlorides with thiobenzamides the solvent seems to be decisive for the course of the reaction. In tertiary formamides the thiobenzamides are desulfurized to nitriles, whereas in CHCI3 or CCI4 amidinium salts (296 Scheme 45) are formed. From trimethylsilyl isocyanate and the fluorinated amine (297) the /V-fluorocarbonylamidine (298) is accessible. ... 

By analogy, ammonium salts should behave as acids in liquid ammonia, since they produce the cation NH4 (the solvo-cation ), and soluble inorganic amides (for example KNHj, ionic) should act as bases. This idea is borne out by experiment ammonium salts in liquid ammonia react with certain metals and hydrogen is given off. The neutralisation of an ionic amide solution by a solution of an ammonium salt in liquid ammonia can be carried out and followed by an indicator or by the change in the potential of an electrode, just like the reaction of sodium hydroxide with hydrochloric acid in water. The only notable difference is that the salt formed in liquid ammonia is usually insoluble and therefore precipitates. 

Uncatalyzed amidations of acids have been realized under solvent-free conditions and with a very important microwave effect [67 a]. The best results were obtained by use of a slight excess of either amine or acid (1.5 equiv.). The reaction involves thermolysis of the previously formed ammonium salt (acid-base equilibrium) and is promoted by nucleophilic attack of the amine on the carbonyl moiety of the acid and removal of water at high temperature. The large difference in yields (MW > A) might be a consequence of interaction of the polar TS with the electric field (Eq. (15 a) and Tab. 3.6). 

Aldonamides are readily prepared by reaction of lactones with liquid ammonia (86,99,100), with ammonium hydroxide (101,102), or by bubbling ammonia gas into alcoholic solutions of the sugar lactones (103-104). Aldonamides of the tetronic adds are stable in aqueous solution (105), but penton- or hexon-amides are hydrolyzed, as shown by the change of the optical rotation of the amide solutions (106). The hydrolysis is catalyzed by acids and bases, and the product was the ammonium salt of the aldonic acid. 

In the following we shall focus on heterogeneous acid-base reactions. One of the best known case studies is the reaction of crystalline benzoic acid with ammonia to form 1 1 ammonium salts [19, 20]. Crystalline p-chlorobenzoic anhydride reacts with gaseous ammonia to give the corresponding amide and ammonium salt [22] a similar reaction has been investigated in the case of optically active cyclopropanecarboxylic acid crystals [23]. 

A vigorously stirred suspension of 0.2 to 1 mole of sodium amide in 200 ml of xylene, in which were dissolved 0.1 mole of a,a-diphenyl-7-hexamethyleneimino butyronitrile was boiled for 12 hours. Thereupon the excess of sodium amide was decomposed with water and the xylene layer was separated, washed with water and extracted with hydrochloric acid. This acidic extract was made strongly alkaline with concentrated lye and the separated base was extracted with ether. After drying, the ether was evaporated and the l,l-diphenyl-3-hexamethyleneimino propane distilled in vacuo. The boiling point was 170-174°C/1 mm, the refractive index nD20 = 1.56 36, and the density d420 = 1.009. From the oil obtained several acid additions and quaternary ammonium salts can be obtained by reaction with acids containing a non-toxic anion or esters thereof. The hydrochloric acid salt, for instance, melts at 189-192°C, the methiodide at 174-177°C under decomposition. 

Ammonia is the most widely studied of nonaqueous inorganic solvents. Many reactions occurring in ammonia follow a close parallel to those in aqueous solution. Ammonium salts may be considered as acids, amides as bases, and ammonia complexes as solvated ions. Four reactions in liquid ammonia are listed, together with the corresponding aqueous reactions ... 

Amides can be synthesized directly from carboxylic acids, using heat to drive off water and force the reaction to completion. The initial acid-base reaction of a carboxylic acid with an amine gives an ammonium carboxylate salt. The carboxylate ion is a poor electrophile, and the ammonium ion is not nucleophilic, so the reaction stops at this point. Heating this salt to well above 100 °C drives off steam and forms an amide. This direct synthesis is an important industrial process, and it often works well in the laboratory. 

Activation with sulfonic acid chlorides is more general, rendering amides with the possible participation of symmetric anhydrides after disproportionation. This method has also found use in the synthesis of modem 3-lactam antibiotics. However, in peptide chemistry this activation method leads to unwanted side reactions, like formation of nitriles in the cases of glutamine and asparagine, and racemization. In a convenient one-pot procedure, the carboxylic acids are activated by sulfonyl chlorides under solid-liquid phase transfer conditions using solid potassium carbonate as base and a lipophilic ammonium salt as catalyst. ... 

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