Addition-Elimination Mechanism of Nucleophilic Acyl Substitution

21-5 Interconversion of Add Derivatives by Nucleophilic Acyl Substitution 995 Addition-Elimination Mechanism 

Step 1 Addition of the nucleophile gives a tetrahedral intermediate. 

EXAMPLE Base-catalyzed transesterification of an ester, cyclopentyl benzoate. Step 1 Addition of the nucleophile gives a tetrahedral intermediate. 

Step 2 Elimination of the leaving group regenerates the carbonyl group. 

PROBLEM-SOLVING /-fC Hf This mechanism applies to most of the reactions in this chapter. 

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Key Mechanism 21-1 Addition-Elimination Mechanism of Nucleophilic Acyl Substitution 998 Mechanism 21-2 Conversion of an Acid Chloride to an Anhydride 1001... 

Ammonia and amines react with acid chlorides to give amides, also through the addition-elimination mechanism of nucleophilic acyl substitution. A carboxylic acid is efficiently converted to an amide by forming the acid chloride, which reacts with an amine to give the amide. A base such as pyridine or NaOH is often added to prevent HC1 from protonating the amine. 

MECHANISM 21-1 Addition-Elimination Mechanism of Nucleophilic Acyl Substitution... 

As we study these conversions of acid derivatives, it may seem that many individual mechanisms are involved. But all these mechanisms are variations on a single theme the addition-elimination mechanism of nucleophilic acyl substitution (Key Mechanism 21-1). These reactions differ only in the nature of the nucleophile, the leaving group, and proton transfers needed before or after the actual substitution. As we study these mechanisms, watch for these differences and don t feel that you must learn each specific mechanism. 

All the mechanisms in this section are variations of the addition-elimination mechanism of nucleophilic acyl substitution. You should be able to draw any of these mechanisms without having to memorize them. 

Hydrolysis at unsaturated carbon occurs by a two-step process (1) nucleophilic addition at the acyl group [RC(0)] to give a tetrahedral intermediate (2.52) and (2) elimination of the leaving group (2.53). This reaction mechanism is referred to as the addition-elimination mechanism or nucleophilic acyl substitution. 

The conversion of an anhydride to an amide illustrates the mechanism of nucleophilic acyl substitution with an anhydride as starting material (Mechanism 22.4). Besides the usual steps of nucleophilic addition and elimination of the leaving group, an additional proton transfer is needed. 

The mechanism of nucleophilic acyl substitution is a major emphasis of this chapter. As the preceding equation indicates, the reaction proceeds in two stages. In the first stage, nucleophilic addition to the carbonyl group occurs to give a tetrahedral intermediate. The second stage restores the carbonyl group by elimination. Experimental support exists for several different mechanisms of nucleophilic acyl substitution. Because most reactions of this type involve tetrahedral intermediates, only mechanisms based upon them will be presented in this chapter. 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

First consider the base-catalyzed transesterification of ethyl benzoate with methanol. This is a classic example of nucleophilic acyl substitution by the addition-elimination mechanism. Methoxide ion is sufficiently nucleophilic to attack the ester carbonyl group. Ethoxide ion serves as a leaving group in a strongly exothermic second step. 

The mechanism for the Fischer esterification involves the usual two steps of nucleophilic acyl substitution—that is, addition of a nucleophile followed by elimination of a leaving group. 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

From a chemical point of view, amide and ester bonds have comparable structural and spectroscopic features and are hydrolyzed by the same general mechanism, i.e., a nucleophilic acyl substitution involving an addition-elimination sequence (see Chapt. 3). However, in a given structure, the amide... 

The mechanism of ester hydrolysis in acid (shown in Mechanism 22.8) is the reverse of the mechanism of ester synthesis from carboxylic acids (Mechanism 22.6). Thus, the mechanism consists of the addition of the nucleophile and the elimination of the leaving group, the two steps common to all nucleophilic acyl substitutions, as well as several proton transfers, because the reaction is acid-catalyzed. 

Acid chlorides react with alcohols to give esters through a nucleophilic acyl substitution by the addition-elimination mechanism discussed on the previous page. Attack by the alcohol at the electrophilic carbonyl group gives a tetrahedral intermediate. Loss of chloride and deprotonation give the ester. 

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. 

The net result of this process is substitution of the —OR group of the alcohol for the —OH group of the acid. Hence the reaction is referred to as nucleophilic acyl substitution. But the reaction is not a direct substitution. Instead, it occurs in two steps (1) nucleophilic addition, followed by (2) elimination. We will see in the next and subsequent sections of this chapter that this is a general mechanism for nucleophilic substitutions at the carbonyl carbon atoms of carboxylic acid derivatives. 

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