Nucleophilic acyl substitution reaction esters

The carbon-sulfur bond of a thioester is rather long—typically on the order of 180 pm—and delocalization of the sulfur lone-pair electrons into the rr orbital of the carbonyl group is not as effective as in esters. Nucleophilic acyl substitution reactions of thioesters occur faster than those of simple esters. A number of important biological processes involve thioesters several of these are described in Chapter 26. 

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... 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

Problem 21.9 How might you prepare the following esters using a nucleophilic acyl substitution reaction of an acid chloride ... 

Ester hydrolysis is common in biological chemistry, particularly in the digestion of dietary fats and oils. We ll save a complete discussion of the mechanistic details of fat hydrolysis until Section 29.2 but will note for now that the reaction is catalyzed by various lipase enzymes and involves two sequential nucleophilic acyl substitution reactions. The first is a trcinsesterificatiori reaction in which an alcohol gioup on the lipase adds to an ester linkage in the tat molecule to give a tetrahedral intermediate that expels alcohol and forms an acyl... 

Amides, like esters, are abundant in all living organisms—proteins, nucleic acids, and many pharmaceuticals have amide functional groups. The reason for this abundance of amides, of course, is that they are stable to the conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions. 

Fischer esterification reaction (Section 21.3) The acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol to yield an ester. 

The intermediate o-bromo acid bromide undergoes a nucleophilic acyl substitution reaction with methanol to give an a-bromo ester. 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

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

Claisen condensation reaction (Section 23.7) a nucleophilic acyl substitution reaction that occurs when an ester enolate ion attacks the carbonyl group of a second ester molecule. The product is a p-keto ester. 

Carboxylic acid derivatives such as esters and amides undergo nucleophilic acyl substitution reactions with the ketone dianion derived fiom benzophenone, providing modest yields of the corresponding carbonyl products (equations 102 and 103). Benzhydrol is a significant by-product in these reactions. 

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. 

Acetyl coenz3 ine A (usually abbreviated acetyl CoA) is the most common thiol ester in nature. Acetyl CoA is a much more complex molecule than acetyl chloride or acetic anhydride, yet it serves exactly the same purpose as these simpler reagents. Nature uses acetyl CoA as a reactive acyl-ating agent in nucleophilic acyl substitution reactions. 

Nature employs nucleophilic acyl substitution reactions in the biosynthesis of many molecules, using thiol esters for the purpose. Acetyl coenzyme A (acetyl CoA) is a complex thiol ester that is employed in living systems to acetylate amines and alcohols. 

Acyl transfer. Acetyl dihydrolipoamide, a thiol ester, undergoes a nucleophilic acyl substitution reaction with coenzyme A to yield acetyl CoA plus dihydrolipoamide. The dihydrolipoamide is then oxidized back to lipoamide by FAD, and the FADH2 that results is in turn oxidized back to FAD NAD ... 

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