Nucleophilic acyl substitution reaction reactivity

Amides are the least reactive caiboxyhc acid deiivative and the only nucleophilic acyl substitution reaction they undeigo is hydrolysis Amides are fanly stable m water but the amide bond is cleaved on heating m the presence of strong acids 01 bases Nomi nally this cleavage produces an amine and a caiboxyhc acid... 

Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition step is generally the rate-limiting one. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process. 

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

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. 

Electrostatic potential maps of a typical amide (acetamide) and an acyl azide (acetyl azide) are shown. Which of the two do you think is more reactive in nucleophilic acyl substitution reactions Explain. 

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. 

Steps 1-2 of Figure 29.5 Acyl Transfers The starting material for fatty-acid synthesis is the thioesteT acetyl CoA, the ultimate product of carbohydrate breakdown, as we ll see in Section 29.6. The synthetic pathway begins with several priming reactions, which transport acetyl CoA and convert it into more reactive species. The first priming reaction is a nucleophilic acyl substitution reaction that converts acetyl CoA into acetyl ACP (acyl carrier protein). The reaction is catalyzed by ACP transacyla.se. 

Following the formation of malonyl CoA, another nucleophilic acyl substitution reaction occurs in step 4 to form the more reactive malonyl ACP, thereby binding the malonyl group to an ACP arm of the multienzyme synthase. At this point, both acetyl and malonyl groups are bound to the enzyme, and the stage is set for their condensation. 

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

According to the electrostatic potential maps, the carbonyl carbon of acetyl azide is more electron-poor and therefore more reactive in nucleophilic acyl substitution reactions. Resonance donation of nitrogen lone-pair electrons to the carbonyl group is greater in an amide than in an acyl azide. 

Step 4 is aiMther nucleophilic acyl substitution reaction that converts malomyt CoA into the more reactive malonyl ACP... 

Explain why trichloroacetic anhydride [(Cl3CC0)20] is more reactive than acetic anhydride [(CH3C0)20] in nucleophilic acyl substitution reactions. 

Penicillin and related P-lactams kill bacteria by a nucleophilic acyl substitution reaction. All penicillins have an unreactive amide side chain and a very reactive amide that is part of a p-lactam. The P-lactam is more reactive than other amides because it is part of a strained, four-membered ring that is readily opened with nucleophiles. 

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. 

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... 

Amides are the least reactive of the carboxylic acid derivatives they can be prepared from any of the other acid derivatives. Hydrolysis, either acid- or base-catalyzed, to form acids is the only nucleophilic acyl substitution reaction. 

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 undergo nucleophilic acyl substitution reactions only when they are in their acidic forms. The basic form of a carboxylic acid does not undergo nucleophilic acyl substitution reactions because the negatively charged carboxylate ion is resistant to nucleophilic attack (Section 17.12). Tbus, carboxylate ions are even less reactive toward nucleophilic acyl substitution reactions than are amides. 

Thioesters are the most common forms of activated carboxylic acids in a cell. Although thioesters hydrolyze at about the same rate as oxygen esters, they are much more reactive than oxygen esters toward attack by nitrogen and carbon nucleophiles. This allows a thioester to survive in the aqueous environment of the cell—without being hydrolyzed—waiting to be a substrate in a nucleophilic acyl substitution reaction. 

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