Carboxylic acids nucleophilic addition-elimination

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

CHAPTER 17 CARBOXYLIC ACIDS AND THEIR DERIVATIVES Nucleophilic Addition-Elimination at the Acyl Carbon... 

The reactions of carboxylic acids and their derivatives are characterized by nucleophilic addition—elimination at their acyl (carbonyl) carbon atoms. The result is a substitution at the acyl carbon. Key to this mechanism is formation of a tettahedtal intermediate that returns to a carbonyl group after the elimination of a leaving group. We shall encounter many reactions of this general type, as shown in the following box. 

As we begin now to explore the syntheses of carboxylic acid derivatives, we shall find that in many instances one acid derivative can be synthesized through a nucleophilic addition—elimination reaction of another. The order of reactivities that we have presented gives us a clue as to which syntheses are practical and which are not. In general, less reactive acyl compounds can be synthesissed from more reactive ones, but the reverse is usually difficult and, when possible, requires special reagents. 

These reactions all involve nucleophilic addition-elimination by a chloride ion on a highly reactive intermediate a protonated acyl chlorosulfite, a protonated acyl chloro-phosphite, or a protonated acyl chlorophosphate. These intermediates contain even better acyl leaving groups than the acyl chloride product. Thionyl chloride, for example, reacts with a carboxylic acid in the following way ... 

Amides can be prepared in a variety of ways, starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylate salts. All of these methods involve nucleophilic addition—elimination reactions by ammonia or an amine at an acyl carbon. As we might expect, acid chlorides are the most reactive and carboxylate anions are the least. 

The reactions of carboxylic acids and their derivatives are summarized here. Many (but not all) of the reactions in this summary are acyl substitution reactions (they are principally the reactions referenced to Sections 17.5 and beyond). As you use this summary, you will find it helpful to also review Section 17.4, which presents the general nucleophilic addition-elimination mechanism for acyl substitution. It is instructive to relate aspects of the specific acyl substitution reactions below to this general mechanism. In some cases proton transfer steps are also involved, such as to make a leaving group more suitable by prior protonation or to transfer a proton to a stronger base at some point in a reaction, but in all acyl substitution the essential nucleophilic addition-elimination steps are identifiable. 

CHAPTER 17 CARBOXYLIC ACIDS AND THEIR DERIVATIVES Nucleophilic Addition-Elimination at the Acyl Carbon 17.53 An alternative synthesis of ibuprofen is given below. Supply the structural formulas for compounds A-D ... 

The aromatic amine undergoes a nucleophilic addition-elimination reaction at the sulfonyl group, with loss of chloride this generates a sulfonamide. The basic conditions of this reaction gives a carboxylate product, which is reprotonated on acidic work-up. 

The functional groups of acyl substitution reactions all relate to carboxylic acids. They include acyl chlorides, anhydrides, esters, amides, thioesters, carboxylic acids themselves, and others that we shall study in this chapter. In Special Topic C we shall see how acyl substitution reactions are used to synthesize polymers such as nylon and Mylar. In Special Topic E we shall consider the biosynthesis of fatty acids and other biological molecules by acyl substitution reactions. Although many functional groups participate in acyl substitution reactions, their reactions are all readily understandable because of the common mechanistic theme that unites them nucleophilic addition-elimination at an acyl carbon. 

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