Acid Anhydrides to Amides

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

MDA reacts with acid anhydrides to form amides. In the reaction with maleic anhydride both of the amino hydrogens are replaced to form the imide, A[,Ar-(methylenedi-/)-phenylene) dimaleimide [1367-54-5]... 

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. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

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. 

Carboxylic acids undergo reactions to produce derivatives of the acid. The most common derivatives formed are esters, acid halides, acid anhydrides, and amides. 

Figure 10.10 The synthesis of 2R-methylbutanoic acid, illustrating the use of a chiral auxiliary. The chiral auxiliary is 2S-hydroxymethyltetrahydropyrrole, which is readily prepared from the naturally occurring amino acid proline. The chiral auxiliary is reacted with propanoic acid anhydride to form the corresponding amide. Treatment of the amide with lithium diisopropyla-mide (LDA) forms the corresponding enolate (I). The reaction almost exclusively forms the Z-isomer of the enolate, in which the OLi units are well separated and possibly have the configuration shown. The approach of the ethyl iodide is sterically hindered from the top (by the OLi units or Hs) and so alkylation from the lower side of the molecule is preferred. Electrophilic addition to the appropriate enolate is a widely used method for producing the enantiomers of a-alkyl substituted carboxylic acids...

Esterification Using Diazomethane 966 Conversion of an Acid Chloride to an Anhydride 1001 Conversion of an Acid Chloride to an Ester 1001 Conversion of an Acid Chloride to an Amide 1002 Conversion of an Acid Anhydride to an Ester 1002 Conversion of an Acid Anhydride to an Amide 1003 Conversion of an Ester to an Amide (Ammonolysis of an Ester) 1003 Transesterification 1008 Saponification of an Ester 1010 Basic Hydrolysis of an Amide 1012 Acidic Hydrolysis of an Amide 1012... 

Reacts with acid chlorides and acid anhydrides to yield amides (Sections 21.4 and 21.5). 

Another way to form a-aminoketones from a-amino acids is via the Dakin-West reaction, in which amino acids are treated with aliphatic acid anhydrides to give ketone amides. Thus, reaction of ( )-phenylalanine with the appropriate aliphatic acid anhydrides followed by acidic hydrolysis afforded keto-amide 1271. Cyclization of 1272 with potassium cyanate gave 5-alkyl-4-benzyl-l,3-dihydroimidazol-2-ones 1273 (Scheme 322) <2002JHC375>. 

The addition of alcohols to nitrilium salts gives rise to formation of alkoxymethyleneiminium salts, which react with bases to yield imido esters (231 Scheme 33). - By deprotonation of carboxylic acid amides ambident anions are formed, which can be alkylated in the presence of silver ions to give imido esters, e.g. (232). " Secondary amides react with trifluoroacetic acid anhydride or trifluorosulfonic acid anhydride to give mixed anhydrides of imidic acids (233). ... 

Sodium aluminohydride (NaAlH4, SAH) in THF is somewhat less reactive than LAH toward carboxylic acids, anhydrides, epoxides, amides, and nitro compounds [CBS], and it can be used for selective reductions. However, it is as sensitive to moisture as LAH so similar precautions must be taken. 

Amines are weak bases. They react with water to liberate hydroxide ions, and they react with acids to form salts. Amines react with acid chlorides and acid anhydrides to form amides. 

Preparation of acetaminophen involves treating an amine with an acid anhydride to form an amide. In this case, p-aminophenol, the amine, is treated with acetic anhydride to form acetaminophen (p-acetamidophenol), the amide. 

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