General Mechanism for Nucleophilic Acyl Substitution

Nucleophilic acyl substitutions follow a two-stage mechanism outlined in the introduction and proceed by way of a tetrahedral intermediate (TI). 

We saw this theme before in Section 18.14 when we presented the mechanism of the Fischer esterification. As was the case then, formation of the tetrahedral intermediate is rate-determining. 

It is important to remember that each stage can consist of more than one elementary step. Therefore, a complete mechanism can have many steps and look complicated if 

The first stage of the mechanism for nucleophilic acyl substitution is exactly the same as for nucleophilic addition to the carbonyl group of an aldehyde or ketone. Many of the same nucleophiles that add to aldehydes and ketones—water (Section 17.6), alcohols (Section 17.8), amines (Sections 17.10-17.11)—add to the carbonyl groups of carboxylic acid derivatives. 

The features that complicate the mechanism of nucleophilic acyl substitution are almost entirely related to acid-base chemistry. We try to keep track, as best we can, of the form in which the various species— reactants, intermediates, and products— exist under the reaction conditions. 

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The general mechanism for nucleophilic acyl substitution is a two-step process nucleophilic attack followed by loss of the leaving group, as shown in Mechanism 22.1. 

The mechanism for this reaction has the usual two steps of the general mechanism for nucleophilic acyl substitution presented in Section 22.7—addition of the nucleophile followed by loss of a leaving group—plus an additional step involving proton transfer (Mechanism 22.9). 

Section 17.7 General Mechanism for Nucleophilic Acyl Substitution Reactions... 

The general mechanism for nucleophilic acyl substitution is a two-step process nucleophilic... 

Nucleophilic acyl substitutions are also called acyl transfer reactions because they transfer the acyl group from the leaving group to the attacking nucleophile. The following is a generalized addition-elimination mechanism for nucleophilic acyl substitution under basic conditions. 

Similar experiments have indicated the reversible formation of tetrahedral intermediates in hydrolysis of other esters, amides, anhydrides, and acid chlorides, and are the basis of the general mechanism we have shown for nucleophilic acyl substitution. 

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. 

Acid derivatives differ in the nature of the nucleophile bonded to the acyl carbon —OH in the acid, —Cl in the acid chloride, —OR in the ester, and —NH2 (or an amine) in the amide. Nucleophilic acyl substitution is the most common method for interconverting these derivatives. We will see many examples of nucleophilic acyl substitution in this chapter and in Chapter 21 ( Carboxylic Acid Derivatives ). The specific mechanisms depend on the reagents and conditions, but we can group them generally according to whether they take place under acidic or basic conditions. 

The add chlorides prepared in this fashion are often not isolated and purified, but rather are used directly in a subsequent reaction. This is possible because both of the side products, HCl and SO2, are gases and readily lost or removed from the mixture. For example, if an amide is the desired product, then the crude acid chloride is simply allowed to react with an excess of an amine. An excess of the amine is used to neutralize the HCl that is generated during the preparation of the acid chloride (Eq. 20.7) and by the reaction of the acid chloride with the amine (Eq. 20.6). Like 18, acid chlorides are highly reactive, and they tend to undergo nucleophilic acyl substitution according to the general mechanism shown in Equation 20.2. 

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. 

A kinetic smdy of the acylation of ethylenediamine with benzoyl chloride (110) in water-dioxane mixtures at pH 5-7 showed that the reaction involves mainly benzoylation of the monoprotonated form of ethylenediamine. Stopped-flow FT-IR spectroscopy has been used to study the amine-catalysed reactions of benzoyl chloride (110) with either butanol or phenol in dichloromethane at 0 °C. A large isotope effect was observed for butanol versus butanol-O-d, which is consistent with a general-base-catalysed mechanism. An overall reaction order of three and a negligible isotope effect for phenol versus phenol- /6 were observed and are consistent with either a base- or nucleophilic-catalysed mechanism. Mechanistic studies of the aminolysis of substituted phenylacetyl chlorides (111) in acetonitrile at —15 °C have revealed that reactions with anilines point to an associative iSN2 pathway. ... 

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