Acid anhydride, amides from reaction with amines

Amino acids exhibit chemical reactions that are typical of both amines and carboxylic acids. For example, the acid can be converted to an ester by the Fischer method. This reaction requires the use of an excess of acid because one equivalent is needed to react with the amino group of the product. As another example, the amine can be converted to an amide by reaction with acetic anhydride. Additional examples are provided by the reactions that are used in the preparation of peptides from amino acids described in Section 26.7 ... 

In the first case, reaction with amines leads to amides amido acids formed when amines react with cyclic anhydrides can be recyclized to cyclic imides (p. 344). When mixed acyclic or asymmetrical cyclic anhydrides react, a mixture of products can be formed, although the stronger acid usually gives an ester (or amide) (56). Reaction of alcohols with anhydrides very often takes place even in the cold certain anhydrides, however, are resistent to heat and can be crystallized from ethanol (57) they can be cleaved by heating with sodium ethoxide in ethanol or benzene. If the acids formed by hydrolysis are solid and suitable for identification, this procedure can be considered as the simplest for identification purposes. When anhydrides of liquid acids are to be identified, the reaction with aromatic amines is generally employed mixed anhydrides are best identified by chromatography of acids formed on alkaline hydrolysis. 

Other Rea.ctlons, The anhydride of neopentanoic acid, neopentanoyl anhydride [1538-75-6] can be made by the reaction of neopentanoic acid with acetic anhydride (25). The reaction of neopentanoic acid with acetone using various catalysts, such as titanium dioxide (26) or 2irconium oxide (27), gives 3,3-dimethyl-2-butanone [75-97-8] commonly referred to as pinacolone. Other routes to pinacolone include the reaction of pivaloyl chloride [3282-30-2] with Grignard reagents (28) and the condensation of neopentanoic acid with acetic acid using a rare-earth oxide catalyst (29). Amides of neopentanoic acid can be prepared direcdy from the acid, from the acid chloride, or from esters, using primary or secondary amines. 

Conversion of Acid Anhydrides into Amides Acetic anhydride is also commonly used to prepare iV-substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts rather than the less nucleophilic -OH group. 

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. 

Solid cyclic carboxylic anhydrides react with gaseous ammonia to give amide ammonium salts with quantitative yield. This has been observed with the labile Diels-Alder adduct 259 [25] (Scheme 38). Aliphatic amine vapors are equally able to open anhydride rings to form the amide salts from where the free amide acids can be obtained in 100% yield. The reaction of 261 with ethylamine to give 262 is an example of a large-scale preparative application [11-12]. Conversely, solid pyromellitic bis-anhydride (263) and methylamine vapor react exother-mally (rise to 95 °C) and quantitatively to yield the tetraamide 264. Interest-... 

Reaction CXLI. Action of Acids, Acid Anhydrides and Chlorides on Primary and Secondary Amines.—Substituted amides are usually prepared by treating amines with organic acids, or with acyl chlorides or anhydrides. When the acid is used a salt is first formed from which a molecule of water is eliminated on further heating. 

Amides. Amides can be prepared in one step from a carboxylic acid and an amine by reaction with 1 (1 equiv.) and triethylamine (2 equiv.) in CH2C12 at 25°. Presumably a mixed anhydride is first formed, which reacts subsequently with the amine. A variation involves conversion of the carboxylic acid into the carboxylic anhydride by reaction with 1 (0.5 equiv.) and triethylamine subsequent addition of the amine results in the formation of the amide. Yields are generally greater than... 

The latter, on reaction with methylamine yielded via the P-epoxide 373, the trans-a aminoalcohol 374, which was N-acylated to the amide 375. Acid-catalysed dehydration of the tertiary alcohol 375, led to the olefin 375, from which the key radical precursor, the chlorothioether377 was secured in quantitative yield by reaction with N-chlorosuccinimide. In keeping with the earlier results recorded for structurally related compounds, 377 on heating in the presence of ruthenium dichloride and triphenylphosphine also underwent a 5-exo radical addition to generate the cyclohexyl radical 378 which recaptured the chlorine atom to furnish the a-chloro-c/5-hydroindolone 379. Oxidation of thioether 379 gave the corresponding sulfoxide 380, which on successive treatment with trifluoroacetic anhydride and aqueous bicarbonate led to the chloro-a-ketoamide 381. The olefin 382 resulting from base induced dehydrochlorination of 381, was reduced to the hydroxy-amine 383, which was obtained as the sole diastereoisomer... 

Synthesis of Amides Amides are the least reactive acid derivatives, and they can be made from any of the others. In the laboratory, amides are commonly synthesized by the reaction of an acid chloride (or anhydride) with an amine. The most common industrial synthesis involves heating an acid with an amine (at high temperatures, in the absence of oxygen) to drive off water and promote condensation. This simple industrial technique rarely works well in the laboratory, but it may succeed with the use of a coupling reagent (Section 24-11). Esters react with amines and ammonia to give amides, and the partial hydrolysis of nitriles also gives amides. 

Amides with an acyl group derived from acetic acid are called acetamides. Acetamides are generally produced from the reactions of acetic anhydride with amines. 

Related anchored l,l,3,3-tetraphenyl-2-oxa-l,3-diphospholanium bis-triflate (39) has been prepared by reaction of brominated poly(styrene-co-divinylbenzene) resin 38 with the phosphorous anion generated from l,2-bis(diphenylphosphino)ethane and sodium naphthalenide followed by further oxidation and reaction with triflic anhydride (Scheme 7.13) [55]. This supported reagent has also been employed, to a lesser extent than 37, for the formation of esters and amides by reaction of carboxylic acids with primary alcohols and amines, respectively. 

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