Amides from ammonium carboxylates

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. ... 

Amides are sometimes prepared directly from carboxylic acids and amines by a two step process The first step is an acid-base reaction m which the acid and the amine combine to form an ammonium carboxylate salt On heating the ammonium carboxy late salt loses water to form an amide... 

The mechanism of amide formation is a source of insight into the properties of carboxylic acids and amines. Initially, we might expect an amine to act as a base and simply accept a proton from the carboxylic acid. Indeed, that does happen, and a quaternary ammonium salt is formed when the reagents are mixed in the absence of a solvent. For example,... 

An amino acid protected only at the N atom and a different amino acid in which only the C02H group is protected do not react with each other to form a peptide bond. On the contrary, they form an ammonium carboxylate in a fast acid/base reaction (Figure 6.29). Ammonium car-boxylates can in principle be converted into amides by strong heating. Thus, for example, in the industrial synthesis of nylon-6,6, the diammonium dicarboxylate obtained from glutamic acid and hexamethylenediamine is converted to the polyamide at 300 °C. However, this method is not suitable for peptide synthesis because there would be too many undesired side 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. 

Polymer-bound reagents have also been used. The synthetically important Weinreb amides [RCON(Me)OMe, see 16-82] can be prepared from the carboxylic acid and MeO(Me)NH HCl in the presence of tributylphosphine and 2-pyridine-A -oxide disulfide. Di(2-pyridyl)carbonate has been used in a related reaction that generates amides directly. The reaction of a carboxylic acid and imidazole under microwave irradiation gives the amide. Microwave irradiation of a secondary amine, formic acid, 2-chloro-4,6-dimethoxy[l,3,5]tria-zine, and a catalytic amount of DMAP (4-dimethylaminopyridine) leads to the formamide. ° Ammonium bicarbonate and formamide converts acids to amides with microwave irradiation. Lactams are readily produced from y- or 8-amino acids, for example. 

The ammonolysis of acyl chlorides is commonly employed whenever the preparation of an amide is desired for the identification of a carboxylic acid. The acyl chloride is prepared and treated with aqueous ammonia, or, if the amide is very soluble in water, with ammonia in benzene. In the latter case the ammonium chloride is filtered off, and the amide obtained by evaporation of the benzene with powdered ammonium carbonate. The preparation of amides from carboxylic acids is based upon the formation of an equilibrium mixture when the ammonium salts of the acid are heated ... 

E Amides from Carboxylic Acids and Ammonium Carboxylates... 

Ammonium polysulfide Carboxylic acid amides from a-subst. carboxylic acids... 

Ammonium acetate Carboxylic acid amides from carboxylic acid chlorides... 

The O is removed from the carboxylate group of valine and two H atoms are removed from the ammonium ion in threonine to form water. The C=0 part of vahne and the N—H part of threonine are joined, which gives a peptide (amide) bond in the dipeptide. 

Recently it has been shown the possibility of formation of ionic liquids from eutectic mixtures of quaternary ammonium salt such as choline chloride (2-hydroxy-ethyl-trimethyl ammonium chloride) with a hydrogen bond donor species such as amides, glycols or carboxylic adds ( Abbott et al., 2003 Endres, 2002 Endres et al., 2008 Mukhopadhyay et al., 2005 Wasserscheid Welton, 2007). These media, also known as "deep eutectic solvents", have been further used to electrodeposit a large range of metals and alloys induding Zn and Zn alloys, Cr, Sn and Sn alloys, Cu and Ag ( Abbott et al., 2003 Abbott et al., 2006 Abbott et al, 2007 Cojocaru et al., 2009 Endres et al., 2008 Florea et al, 2010). 

Notice that salt formation, though very favorable, is nonetheless reversible. Upon heating, a slower but thermodynamically favored reaction between the acid and the amine can take place. The acid and the amine are removed from the equilibrium, and eventually salt formation is completely reversed. In this second mode of reaction, the nitrogen acts as a nucleophile and attacks the carbonyl carbon. Completion of an addition-elimination sequence leads to the amide. Although it is convenient, this method suffers from the high temperatures required to reverse ammonium carboxylate formation. Therefore, better procedures rely on the use of activated carboxylic acid derivatives, such as acyl chlorides (Chapter 20). 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

Carboxymethylcellulose, polyethylene glycol Combination of a cellulose ether with clay Amide-modified carboxyl-containing polysaccharide Sodium aluminate and magnesium oxide Thermally stable hydroxyethylcellulose 30% ammonium or sodium thiosulfate and 20% hydroxyethylcellulose (HEC) Acrylic acid copolymer and oxyalkylene with hydrophobic group Copolymers acrylamide-acrylate and vinyl sulfonate-vinylamide Cationic polygalactomannans and anionic xanthan gum Copolymer from vinyl urethanes and acrylic acid or alkyl acrylates 2-Nitroalkyl ether-modified starch Polymer of glucuronic acid... 

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