Nucleophilic acyl substitution of esters

Nucleophilic acyl substitutions of esters are summarized in Table 19.4. 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 of nucleophilic acyl substitution comes from studies carried out on esters. The following sections describe those mechanistic studies. 

Thioesters undergo the same kinds of reactions as esters and by similar mechanisms Nucleophilic acyl substitution of a thioester gives a thiol along with the product of acyl transfer For example... 

Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to that we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate that then undergoes hydrolysis. 

The mechanism ofthe Claitten condensation is Btnjlar to that of the aldo condensation. As 5hown in Fi re 23,, the Claison condensation inyiAr the nucleophilic acyl substitution of an ester enoltto ton on the carbonyl group of a second ester molecule ... 

Nucleophilic Acyl Substitutions. Samarium(II) iodide facilitates the highly selective intramolecular nucleophilic acyl substitution of halo esters (eqs 19 and 20). ... 

In this section, we examine the formation of an enolate anion from one ester, followed by the nucleophilic acyl substitution of the enolate anion at the carbonyl carbon of another ester. One of the first of these reactions discovered was the Claisen condensation, named after its discoverer, German chemist Ludwig Qaisen (1851—1930). We illustrate a Claisen condensation by the reaction between two molecules of ethyl acetate in the presence of sodium ethoxide, followed by acidification, to give ethyl acetoacetate (note that, in this and many of the equations that follow, we abbreviate the ethyl group as Et) ... 

Release of 6-deoxyerythronolide B from the PKS is catalyzed by the ending thioesterase module. A serine residue on the TE module first carries out a nucleophilic acyl substitution on the ACP-hound heptaketide, and the acyl enzyme that results undergoes lactonization. A histidine residue in the TE acts as base to catalyze nucleophilic acyl substitution of the serine ester by the terminal -OH group in the heptaketide (Figure 25.21). 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

The mechanism of acid catalyzed ester hydrolysis is presented m Figure 20 4 It IS precisely the reverse of the mechanism given for acid catalyzed ester formation m Section 19 14 Like other nucleophilic acyl substitutions it proceeds m two stages A... 

Convincing evidence that ester hydrolysis in base proceeds by the second of these two paths namely nucleophilic acyl substitution has been obtained from several sources In one experiment ethyl propanoate labeled with 0 m the ethoxy group was hydrolyzed On isolating the products all the 0 was found m the ethyl alcohol there was no 0 enrichment m the sodium propanoate... 

The reaction of ammonia and amines with esters follows the same general mech anistic course as other nucleophilic acyl substitution reactions (Figure 20 6) A tetrahe dral intermediate is formed m the first stage of the process and dissociates m the second stage... 

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... 

Nucleophilic acyl substitution (Sections 20 4 20 6 and 20 12) Acylation of am monia and amines by an acyl chloride acid anhydride or ester is an excep tionally effective method for the for mation of carbon-nitrogen bonds... 

As we saw m Chapter 20 thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution They also contain a greater proportion of enol at equilib rmm Both properties are apparent m the properties of acetyl coenzyme A In some reactions it is the carbonyl group of acetyl coenzyme A that reacts m others it is the a carbon atom... 

FIGURE 28 12 Translation of mRNA to an ammo acid sequence of a protein starts at an mRNA codon for methionine Nucleophilic acyl substitution transfers the N formylmethionme residue from Its tRNA to the ammo group of the next ammo acid (shown here as alanine) The process converts an ester to an amide... 

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. 

From acyl chlorides (Sections 15.8 and 20.4) Alcohols react with acyl chlorides by nucleophilic acyl substitution to yield esters. These reactions are typically performed in the presence of a weak base such as pyridine. 

Ester hydrolysis is the most studied and best understood of all nucleophilic acyl substitutions. Esters are fairly stable in neutral aqueous media but are cleaved when heated with water in the presence of strong acids or bases. The hydrolysis of esters in dilute aqueous acid is the reverse of the Eischer esterification (Sections 15.8 and 19.14) ... 

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