Nucleophilic acyl substitution reaction acid anhydrides

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. 

Propose a mechanism for the reaction of benzoic acid with oxalyl chloride. This mechanism begins like the thionyl chloride reaction, to give a reactive mixed anhydride. Nucleophilic acyl substitution by chloride ion gives a tetrahedral intermediate that eliminates a leaving group, which then fragments into carbon dioxide, carbon monoxide, and chloride ion. 

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

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. 

Like all anhydrides, the mixed carboxylic-phosphoric anhydride is a reactive substrate in nucleophilic acyl substitution reactions (Section 21.5). Reaction of 3-phosphoglyceroyl phosphate with ADP occurs with nucleO philic attack on phosphorus and results in transfer of a phosphate group to yield ATP and 3-phosphoglycerate. The process is catalyzed lay the enzyme j phosphoglycerate kinase. Note that the carboxylic acid group is written in its, dissociated form to reflect the state in which it exists at physiological pH. I... 

Nucleophilic Acyl Substitution Reactions of Acid Anhydrides... 

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. 

Carboxylic acids can also be activated for nucleophilic acyl substitution reactions by being converted into anhydrides. Treating a carboxylic acid with a strong dehydrating agent such as P2O5 yields an anhydride. 

A carboxyhc acid derivative will undergo a nucleophilic acyl substitution reaction provided that the newly added group in the tetrahedral intermediate is not a much weaker base than the group that was attached to the acyl group in the reactant. The weaker the base attached to the acyl group, the easier it is for both steps of the nucleophilic acyl substitution reaction to take place. The relative reactivities toward nucleo-phihc acyl substitution acyl halides > acid anhydrides > carboxylic acids and esters > amides > carboxylate ions. 

Acid anhydrides are not as reactive as acid chlorides, but they are still activated toward nucleophilic acyl substitution. Reaction with an alcohol gives an ester. Notice that one of the two acid units from the anhydride is expelled as the leaving group. 

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

In the preparation of amides, acid chlorides or anhydrides may be used to react with the selected amine. It is known that acid chlorides are more reactive than the corresponding anhydrides in this type of nucleophilic acyl substitution reaction. Offer a reasonable explanation for this observation. 

Acyl CoAs, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage (0=P-0-P=0) between phosphopantetheine and adenosine 3, 5 -bisphosphate. (The prefix bis- means two and indicates that adenosine 3, 5 -bisphosphate has two phosphate groups, one on C3 and one on C5. ) Reaction of coenzyme A with an acyl phosphate or acyl adenylate gives the acyl CoA (Figure 16.10). As we saw in Section 16.5 (Figure 16.6), formation of the acyl adenylate occurs by reaction of a carboxylic acid with ATP and is itself a nucleophilic acyl substitution reaction that takes place on phosphorus. 

The characteristic reaction of acyl chlorides acid anhydrides esters and amides is nucleophilic acyl substitution Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral mtermedi ate that dissociates to give the product of substitution... 

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. 

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. 

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