Ammonia, with acyl halides

Primary amides have the general formula RCONH2. They can be prepared by the reaction of ammonia with esters (eq. 10.24), with acyl halides (eq. 10.36), or with acid anhydrides (eq. 10.39). Amides can also be prepared by heating the ammonium salts of acids. 

The first test to be applied to basic compounds is the acylation test Ammonia, primary amines, and secondary amines are readily acylated, whereas tertiary amines usually undergo no similar reaction although in the latter case addition products with acyl halides may be formed. ... 

The Tertiary Amines.—This class of amim s dilTers from ammonia and the primary and secondary airum s in its nonactivity with acyl halides and anhydrides. 

Ammonia and amines are better nucleophiles than water or alcohols because the nitrogen atom is less electronegative than oxygen. Therefore, amines are stronger bases. Because amides are the most stable acyl derivatives, ammonia and amines react with acyl halides, anhydrides, and esters to give amides. 

The treatment of acyl halides with ammonia or amines is a very general reaction for the preparation of amides.The reaction is highly exothermic and must be carefully controlled, usually by cooling or dilution. Ammonia gives unsubstituted amides, primary amines give A-substituted amides, and secondary amines give N,N-disubstituted amides. Arylamines can be similarly acylated. In some cases aqueous... 

By far the most common method for preparation of amides is the reaction of ammonia or a primary or secondary amine with one of the reactive reagents described in Section 3.4.1. When acyl halides are used, some provision for neutralizing the hydrogen halide is necessary, because it will otherwise react with the reagent amine to form the corresponding salt. Acid anhydrides give rapid acylation of most amines and are convenient if available. The Schotten-Bauman conditions, which involve shaking an amine with excess anhydride or acyl chloride and an alkaline aqueous solution, provide a very satisfactory method for preparation of simple amides. 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

The formation of amides can be accomplished by dehydration of the ammonium salts of salicylic acid. The more common method for amines is the reaction of the ester, acyl halide, or anhydride with an amine or ammonia. Each step is fast and essentially irreversible. 

The treatment of acyl halides with ammonia or amines is a very general reaction for the preparation of amides.843 The reaction is highly exothermic and must be carefully controlled,... 

Amides can be obtained from acyl halides, carboxylic anhydrides, or esters with amines or ammonia. The mechanisms of these reactions are very similar to the corresponding reactions of alcohols ... 

Write the equation for the reaction of a given acyl halide or anhydride with a given nucleophile (especially with water, an alcohol, or ammonia). 

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). 

Acid Amides can be produced by acylating ammonia with esters, acid anhydrides, or the acids themselves (above 100 °C) an important product is formamide from methyl formate. Alternatively acid amides can be synthesized by reacting acid halides with ammonia. Catalytic hydrogenation converts the acid amides to primary amines. Ammonia and aldehydes or ketones are the basis for different stable products. With formaldehyde hexamethylenetetramine (urotropine) is obtained with acetaldehyde, ammono acetaldehyde with benzaldehyde, hydrobenzamide with ethylene and propylene oxides, aqueous ammonia reacts to form ethanol- or propanolamine. 

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. ... 

Preparation of diazoketones and their rearrangements during hydrolysis (method 271) and alcoholysis (method 295) are discussed elsewhere. Ammonolysis of diazoketones leads to amides of acids containing one more carbon atom than the original acyl halide. Halogen atoms may be present in a remote position on an aliphatic chain. The reaction is carried out by heating the diazoketone in alcohol or dioxane solution with aqueous ammonia in the presence of silver oxide or silver nitrate catalysts. Substituted acetanilides are formed when aniline is used in place of ammonia. ... 

Caution All apparatus used for the preparation of acyl halides must be perfectly dry, since the reagents as well as the products are decomposed by water. Goggles should be worn throughout the experiment. Benzoyl chloride is a lachrymator, and should be handled with care. Residues should not be thrown into the sink, but washed with ammonia and then poured into a bottle placed in the hood. Care should also be exercised in handling phosphorus and sulfur halides. Do not allow any halide to come in contact with the skin, as they produce severe burns. 

The reaction of an acyl chloride with ammonia or with a primary or secondary amine forms an amide and HCl. The acid generated in the reaction will protonate unreacted ammonia or unreacted amine because they are not nucleophiles, the protonated amines cannot react with the acyl chloride. The reaction, therefore, must be carried out with twice as much ammonia or amine as acyl chloride so that there will be enough amine to react with all the acyl halide. 

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