Ammonia with carboxylic acids

Manufacture of many important amino intermediates used for dyes and other purposes is usually by conversion or replacement of a substituent. For example, as already mentioned, in substituted nitro compounds, the nitro groups may be reduced with iron/hydrochloric acid, hydrogen and catalyst, or zinc in aqueous alkali. Partial reductions can be brought about with sodium sulfide. Amino groups may be introduced by replacing halogens in the aromatic ring. Another approach to amination is by attack on a substituted aromatic compound with ammonia or amines. Thus, for example, direct amination of p-chloronitrobenzene (15a) in the presence of a copper catalyst affords p-nitroaniline (15b) in almost quantitative yield l,4-dichloro-2-nitrobenzene (16) is converted in a similar way to 4-chloro-2-nitroaniline (17). Reactions of ammonia with carboxylic acids or anhydrides are carried out on an industrial scale. 

Tertiary amines also react with carboxylic acids to form an ammonium salt. Triethylamine (NEtg), for example, reacts with hexanoic acid to give an ammonium salt. Heating does not give an amide because there is no possibility for loss of water. Therefore, amides are formed only by heating the reaction products generated by mixing primary and secondary amines, or ammonia, with carboxylic acids. 

The extent of coupling is also influenced by the solvent. In the hydrogenation of aniline over ruthenium oxide, coupling decreased with solvent in the order methanol > ethanol > isopropanol > t-butanol. The rate was also lower in the lower alcohols, probably owing to the inhibiting effect of greater concentrations of ammonia (44). Carboxylic acid solvents increase the amount of coupling (42). 

Amines are derived from ammonia by the replacement of hydrogen atoms with organic groups. Amides result from the condensation of amines with carboxylic acids. Amines and many amides take part in hydrogen bonding. 

Although, the enzymatic reaction of esters with amines or ammonia have been well documented, the corresponding aminolysis with carboxylic acids are rarer, because of the tendency of the reactants to form unreactive salts. For this reason some different strategies have been used to avoid this problem. Normally, this reaction has been used for the preparation of amides of industrial interest, for instance, one of the most important amides used in the polymer industry like oleamide has been produced by enzymatic amidation of oleic acid with ammonia and CALB in different organic solvents [10]. 

Other Gas Reactions. Several other reactive gases or vapours were examined but found to be unsatisfactory. No ester formation ( 1745 cm"1) was found when oxidatized films were exposed to acetic acid or formic acid vapour. Alcohol/carboxylic acid reactions in the solid state have often been suggested as the source of ester products, but not substantiated (4,5). Gaseous ammonia reacted with carboxylic acid groups to give absorptions at 1550 cm"1 [-C(=0)-0 ] and 1300 cm"1 (NHi +). However, these absorptions were very broad and the method inferior to acid measurement by SF. Although N20 did not react with oxidized polyolefins, the reaction of N02 with oxi-... 

In aqueous solutions, calcium chloride undergoes double decomposition reactions with a number of soluble salts of other metals to form precipitates of insoluble calcium salts. For example, mixing solutions of calcium chloride with sodium carbonate, sodium tungstate and sodium molybdate solutions precipitates the carbonates, tungstates, and molybdates of calcium, respectively. Similar precipitation reactions occur with carboxylic acids or their soluble salt solutions. CaCb forms calcium sulfide when H2S is passed through its solution. Reaction with sodium borohydride produces calcium borohydride, Ca(BH4)2. It forms several complexes with ammonia. The products may have compositions CaCl2 2NH3, CaCb dNHs, and CaCb SNHs. 

The cyclocondensation of l,3-amino alcohols with carboxylic acid derivatives is a method often applied for the synthesis of 5,6-dihydro-4/7-l,3-oxazines <1996CHEC-II(6)301 >. Ebsorb-4, a weakly acidic zeolite-type adsorbent with 4 A pore size, proved an efficient catalyst of the cyclization of benzoic acid and 3-aminopropanol <2002TL3985>. In the presence of zinc chloride as a catalyst, the expulsion of ammonia drove the reactions of 3-aminopropanol with nitriles to completion, affording 2-substituted 5,6-dihydro-47f-l,3-oxazines in good yields... 

Preparation of amides Ammonia, 1° and 2° amines react with carboxylic acids to produce, respectively, 1°, 2° and 3° amides, through a nucleophilic acyl substitution reaction. The reaction of ammonia and a carhoxylic acid initially forms a carhoxylate anion and an ammonium cation. Normally the... 

Under suitable conditions, amide formation can take place between an amine and a carboxylic acid, an acyl halide, or an acid anhydride. Along with ammonia, primary and secondary amines yield amides with carboxylic acids or derivatives. Table 33.2 relates the nitrogen base with the amide class (based on the number of alkyl or aryl groups on the nitrogen of the amide). 

Using the principles we ve outlined above, you should be able to see how these compounds can be interconverted by substitution reactions with appropriate nucleophiles. We ve seen that acid chlorides react with carboxylic acids to give acid anhydrides, and with alcohols to give esters. They ll also react with amines (such as ammonia) to give amides. 

This reaction represents the best general method for amide preparation. Cold, concentrated aqueous ammonia is used as in the preparation of iso-butyramide (83%),or the reaction may be carried out by passing dry ammonia into a solution of the acyl halide in anhydrous ether as in the formation of cyclopropanecarboxamide (91%). Separation of the amide from ammonium chloride is usually accomplished by extraction of the amide by organic solvents. Aqueous sodium hydroxide is employed to take up the hydrogen chloride when amine hydrochlorides are used in place of the free amines as in the preparation of N-methylisobutyramide (75%). When phosphorus trichloride is added to a mixture of an amine and a carboxylic acid, phosphazo compounds, RN=PNHR, rather than acyl halides, are believed to be intermediates. These compounds have been shown to react with carboxylic acids to give amides. ... 

A reaction which is applicable to the synthesis of imidazoles substituted at C-4 by sulfur substituents is the interaction of a-chloro-a-phenyl thioketones (prepared from the corresponding diazoketones) with ammonia and carboxylic acids. Although the detailed reaction course is yet uncertain, it bears a close resemblance to the reactions of a-chloro ketones with amides. The method has been used to prepare 2-ethyl-4-methyl-5-phenylthioimidazole (145) using ammonia, propanoic acid and 1-chloro-l-phenylthiopropanone (Scheme 82). 

The reaction of elemental sulfur in pyridine with 1,2-dithiolylium salts has been used for the synthesis of several l,2-dithiole-3-thiones.7 3-Chloro-1,2-dithiolylium salts give l,2-dithiole-3-thiones with sulfur-free bases such as ethanol, ammonia, methyl- and dimethylamine, piperidine, morpholine, and the azide ion.8 These salts form l,2-dithiol-3-ones with carboxylic acids.8... 

Reactions. As with other tertiary alcohols, esterification with carboxylic acids is difficult and esters are prepared with anhydrides (181), acid chlorides (182), or ketene (183). Ca.rba.mic esters may be prepared by treatment with an isocyanate (184) or with phosgene followed by ammonia or an amine (185). 

Ammonia and primary and secondary amines can be acylated by heating them with carboxylic acids. The removal of water occurs within the framework of an equilibrium that affords worthwhile amounts of amide only at temperatures above 100° (usually at 180-200°). So one of the starting materials (acid or amine) is usually taken in excess and the water formed is removed continuously from the reaction mixture. For formylation only, aqueous acid can be used. Yields are mostly good. 

---