Nucleophilic Acyl Substitution in Acid Anhydrides

After acyl halides, acid anhydrides are the most reactive carboxylic acid derivatives. Although anhydrides can be prepared by reaction of carboxylic acids with acyl chlorides as was shown in Table 19.1, the three most commonly used anhydrides are industrial chemicals and are prepared by specialized methods. Phthalic anhydride and maleic anhydride, for example, are prepared from naphthalene and butane, respectively. 

Acetic anhydride Phthalic anhydride Maleic anhydride 

Acid anhydrides contain two acyl groups bonded to the same oxygen. In nucleophilic acyl substitution, one of these acyl groups becomes bonded to the nucleophilic atom. The other acyl group remains on oxygen to become part of a carboxylic acid. 

Acid anhydrides are more stable and less reactive than acyl chlorides. Acetyl chloride, for example, undergoes hydrolysis about 100,000 times more rapidly than acetic anhydride at 25°C. 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated in Table 19.2. Because a more highly stabilized carbonyl group must result in order for nucleophilic acyl substitution to be effective, acid anhydrides are readily converted to carboxylic acids, esters, and amides but not to acyl chlorides. 

TABLE 19.2 Conversion of Acid Anhydrides to Other Carboxylic Acid Derivatives 

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Primary (RNH2) and secondary (R2NH) amines undergo nucleophilic acyl substitution with acid chlorides and anhydrides in pyridine or EtsN to give 2° and 3° amides (see Section 5.5.5). Primary amines (RNH2) react with... 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

Nucleophilic acyl substitutions at the ester carbonyl group are summarized in Table 20.6. Esters are less reactive than acyl chlorides and acid anhydrides. Nucleophilic acyl substitution in esters, especially ester hydrolysis, has been extensively investigated from a mechanistic perspective. Indeed, much of what we know concerning the general topic... 

The reagent commonly used to prepare an acid chloride from a carboxylic acid is thionyl chloride, SOCI2. The reaction probably proceeds via the intermediate mixed anhydride 18 (Eq. 20.7), which is very reactive. Consequently, it undergoes rapid attack by chloride ion via a nucleophilic acyl substitution in which sulfur dioxide and chloride ion are lost and the acid chloride is produced. 

The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. In the most common mechanism, addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution ... 

The first example in Table 20.2 introduces a new aspect of nucleophilic acyl substitution that applies not only to acid anhydrides but also to acyl chlorides, thioesters, esters, and amides. Nucleophilic acyl substitutions can be catalyzed by acids. 

The 7-glutfflnyl phosphate fonned in this step is a mixed anhydride of glutfflnic acid and phosphoric acid. It is activated toward nucleophilic acyl substitution and gives glutamine when attacked by ammonia. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

Notice in both of the previous reactions that only "half" of the anhydride molecule is used the other half acts as the leaving group during the nucleophilic acyl substitution step and produces acetate ion as a by-product. Thus, anhydrides are inefficient to use, and acid chlorides are normally preferred for introducing acyl substituents other than acetyl groups. 

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. 

In general, we can easily accomplish nucleophilic acyl substitutions that convert more reactive derivatives to less reactive ones. Thus, an acid chloride is easily converted to an anhydride, ester, or amide. An anhydride is easily converted to an ester or an amide. An ester is easily converted to an amide, but an amide can be hydrolyzed only to the acid or the carboxylate ion (in basic conditions). Figure 21-9 graphically summarizes these conversions. Notice that thionyl chloride (SOCI2) converts an acid to its most reactive derivative, the acid chloride (Section 20-15). 

Some reactions that can go as basic nucleophilic acyl substitutions actually work much better with an acid catalyst. For example, aspirin is made from salicylic acid and acetic anhydride. When these reagents are mixed, the reaction goes slowly. Addition of a drop of sulfuric acid accelerates the reaction, and it goes to completion in a minute or two. 

Nature uses thiol esters and acyl phosphates in nucleophilic acyl substitution reactions because they are intermediate in reactivity between acid anhydrides and esters. 

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