Acid chlorides with ammonia or amines

Treatment of acid chlorides with ammonia or amines in benzene gives thiazolecarboxamides (71, 77. 78). 

Pyridazinecarboxamides are prepared from the corresponding esters or acid chlorides with ammonia or amines or by partial hydrolysis of cyanopyridazines. Pyridazinecarboxamides with a variety of substituents are easily dehydrated to nitriles with phosphorus oxychloride and are converted into the corresponding acids by acid or alkaline hydrolysis. They undergo Hofmann degradation to give the corresponding amines, while in the case of two ortho carboxamide groups pyrimidopyridazines are formed. 

Amides are also formed by the reaction of an acid chloride with ammonia or an amine ... 

The treatment of sulfonyl chlorides with ammonia or amines is the usual way of preparing sulfonamides. Primary amines give N-alkyl sulfonamides, and secondary amines give N,N-dialkyl sulfonamides. The reaction is the basis of the Hinsberg test for distinguishing between primary, secondary, and tertiary amines. N-Alkyl sulfonamides, having an acidic hydrogen, are soluble in alkali, while N,N-dialkyl sulfon-... 

Reaction of an Acid Chloride with Ammonia or an Amine (Section 14.5A)... 

Ketone formation can also be avoided if one of the functional acyl halogens ia phosgene is blocked. Carbamyl chlorides, readily obtained by the reaction of phosgene with ammonia or amines, are suitable reagents for the preparation of amides ia direct Friedel-Crafts acylation of aromatics. The resulting amides can be hydroly2ed to the corresponding acids (134) ... 

Acid chlorides are very reactive, and they readily react with ammonia, primary amines, or secondary amines to form an amide. Figure 12-26 illustrates the reaction of an acid chloride with ammonia. Replacing one or two of the hydrogen atoms of ammonia with an organic group will result in an N-substituted amide. Tertiary amines react with acid chlorides to form a carboxylic acid and an ammonium salt. 

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. 

This is generally a poor method for preparing amides. A much better method is to convert the acid to an acyl chloride and then treat the acyl chloride with ammonia or an amine (Section 17.8B). 

Prepare methyl ester (a) by Fischer esterification of phenylacetic acid with methanol. Then treat this ester with ammonia to prepare amide (b). Alternatively, treat phenylacetic acid with thionyl chloride (Section 17.8) to give an acid chloride. Then treat this acid chloride with ammonia to give amide (b). Reduction of the amide (b) by LiAlH gives the primary amine (c). Similar reduction of either phenylacetic acid or ester (a) gives alcohol (d). 

Reaction requires two moles of ammonia or amine, one to form the amide and one to neutralize the carboxylic acid by-product. The mechanism is analogous to that of the acid chloride reaction with ammonia or amines. 

Nitriles react with ammonia, or primary or secondary amines in the presence of an acid catalyst to give amidines (Scheme 26) (75, 77, 81). The catalysts used are hydrochloric acid and aluminium chloride. The amidines are anthelmintics for animals such as sheep, goats, cattle, horses, and Swine. 

The hydrogenolysis of hydroxamic acids (22) and hydra2ides (23) has also been used to synthesi2e amides. One of the earliest methods for the preparation of amides consists of treating acid chlorides with dry ammonia or an amine (24). 

Succinic acid reacts with urea in aqeous solution to give a 2 1 compound having mp 141°C (116,117), which has low solubiUty in water. A method for the recovery of succinic acid from the wastes from adipic acid manufacture is based on this reaction (118,119). The monoamide succinamic acid [638-32-4] NH2COCH2CH2COOH, is obtained from ammonia and the anhydride or by partial hydrolysis of succinknide. The diamide succinamide [110-14-3], (CH2C0NH2)2, nip 268—270°C, is obtained from succinyl chloride and ammonia or by partial hydrolysis of succinonitrile. Heating succinknide with a primary amine gives A/-alkylsucckiknides (eq. 9). 

When the -OH of a carboxylic acid is replaced by an -NH2, the compound produced is an amide. Amides are neutral to mildly basic compounds. They can be made from acids, acid chlorides, acid anhydrides, and esters by reaction with ammonia or primary and secondary amines. The amide linkage is found in polyamide resins such as nylon. 

Esters are less reactive than acid chlorides and acid anhydrides. They are converted to carboxylic acid hy acid or base hydrolysis, and to another ester by acid or base alcoholysis (transesterification). The 1°, 2° or 3° amides are obtained from esters by treatment with ammonia or 1° or 2° amines, respectively. 

Preparation of amides Ammonia and 1° and 2° amines react with acid chlorides and acid anhydrides to give 1°, 2° and 3° amides, respectively, in the presence of excess pyridine (C5H5N) or triethylamine (Et3N). In the case of acid anhydride, two molar equivalents of ammonia or amines are required. 

Amides are most commonly prepared by reaction of an acyl chloride or an anhydride with ammonia or an amine. Because the by-products of these reactions are acidic, base must also be added to the reaction. An excess of the amine can be employed as the base if it is inexpensive, or the reaction may be done in the presence of sodium hydroxide or some other base. Following are several examples. 

Thiazolecarboxylic acids, esters or acid chlorides react readily with ammonia or various amines, affording the corresponding carboxamides. Dehydration of the amides with phosphorus pentoxide or phosphoryl chloride occurs readily and gives the corresponding nitriles (Scheme 99). Thiazolecarboxylic acid hydrazides are obtained in a similar way, using hydrazine or substituted hydrazines instead of ammonia or amines. The Raney nickel reduction of cyanothiazoles leads to the corresponding amino compounds, the 4-cyano derivative being the isomer most readily reduced. 

Acid chlorides react rapidly with ammonia and amines to give amides. The HC1 generated by the reaction can protonate the amine starting material, so a twofold excess of the amine is required. Alternatively, a base such as pyridine or NaOH may be added with the amine to neutralize the HC1 and avoid having to use a large excess of the amine. 

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