Nucleophilic Acyl Substitution in an Anhydride

Nucleophilic Acyl Substitution in an Anhydride THE OVERALL REACTiON  

Step 1 Nucleophilic addition of p-nitrophenoxide to one of the carbonyl groups of the anhydride gives the conjugate base of the tetrahedral intermediate (Tl). 

Step 2 Expulsion of acetate from Tl restores the carbonyl group. 

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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. 

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. 

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. 

Oxidation converts the hemithioacetal into a thiol ester—an acyl enzyme. Like other esters, this one is prone to nucleophilic acyl substitution. It is cleaved, with phosphate ion as nucleophile, to regenerate the sulfhydryl group in the enzyme. The other product is 1,3-diphosphoglycerate. The molecule is (still) a phosphate ester at the 3-position, and has become a mixed anhydride at the 1-position. 

Nucleophilic acyl substitution reactions take place in living organisms just as they take place in the chemical laboratory. The same principles apply in both cases. Nature, however, often uses a thiol ester, RCOSR, as the add derivative because it is intermediate in reactivity between an acid anhydride and an ester. Thiol esters aren t as reactive as anhydrides, yet they re more reactive than typical esters toward nucleophilic attack. 

In Section 17.4 we saw that in a nucleophilic acyl substitution reaction, the nucleophile that forms the tetrahedral intermediate must be a stronger base than the base that is already there. This means that a carboxylic acid derivative can be converted into a less reactive carboxylic acid derivative, but not into one that is more reactive. For example, an acyl chloride can be converted into an anhydride because a carboxylate ion is a stronger base than a chloride ion. 

Offer an explanation of why 2,2,2-trifluoroacetic anhydride is more reactive toward aniline than acetic anhydride in the nucleophilic acyl substitution reaction presented in this experiment. 

Mechanistically, nucleophilic acyl substitutions of anhydrides normally proceed by way of a tetrahedral intermediate. When the nucleophile is an anion, TI is the initial intermediate and its dissociation leads directly to the observed products as shown in Mechanism 19.1 for the reaction ... 

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