Nucleophilic acyl substitution reactions leaving groups

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

This intermediate expels a dtacylglycerol as leaving group in a nucleophilic acyl substitution reaction, giving an acyl enzyme. The dtacylglycerol is protonated by the histidine cation. 

The tetrahedral intermediate expels the serine as leaving group in a second nucleophilic acyl substitution reaction, yielding a free fatty acid. The serine accepts a proton from histidine, and the enzyme has now returned to its starting structure. 

Nucleophilic acyl substitution reaction (Section 21.2) A reaction in which a nucleophile attacks a carbonyl compound and substitutes for a leaving group bonded to the carbonyl carbon. 

This is a typical nucleophilic acyl substitution reaction, with morpholine as the nucleophile and chloride as the leaving group. 

This is a typical nucleophilic acyl substitution reaction, with the amine of the amino acid as the nucleophile and tot-butyl carbonate as the leaving group. The tor-butyl carbonate then loses C02 and gives toi-butoxide, which is protonatecl. 

The presence or absence of a leaving group on the electrophilic carbonyl carbon determines the strucmre of the product. Even though they appear somewhat more complicated, these reactions are often reminiscent of the nucleophilic addition and nucleophilic acyl substitution reactions of Chapters 21 and 22. Four types of reactions are examined ... 

The chemistry of carboxylic acid derivatives is dominated by the nucleophilic acyl substitution reaction. Mechanistically, these substitutions] take place by addition of a nucleophile to the polar carbonyl group of the acid derivative, followed by expulsion of a leaving group from the tetrahedral intermediate. 

Many nucleophilic acyl substitution reactions of carboxylic acids are acid-initiated. For example, in esterification, the carbonyl group is protonated, alcohol attacks to form the tetrahedral intermediate, proton transfers occur, and water leaves. 

You have seen that nucleophilic acyl substitution reactions take place by a mechanism in which a tetrahedral intermediate is formed and subsequently collapses. The tetrahedral intermediate, however, is too unstable to be isolated. How, then, do we know that it is formed How do we know that the reaction doesn t take place by a one-step direct-displacement mechanism (similar to the mechanism of an Sn2 reaction) in which the incoming nucleophile attacks the carbonyl carbon and displaces the leaving group—a mechanism that would not form a tetrahedral intermediate ... 

Acid anhydrides are not as reactive as acid chlorides, but they are still activated toward nucleophilic acyl substitution. Reaction with an alcohol gives an ester. Notice that one of the two acid units from the anhydride is expelled as the leaving group. 

As the electronegative group (Y) can act as a leaving group, carboxylic acid derivatives undergo nucleophilic acyl substitution reactions (i.e. reactions leading to substitution of the Y group by the nucleophile). 

In summary, the mechanism for a nucleophilic acyl substitution reaction involves two core steps— nucleophilic attack and loss of a leaving group. Notice that these are the same two steps involved in an 5 2 process. However, there is one important difference. In an Si,i2 process, the two steps occur in a concerted fashion (simultaneously), but in a nucleophihc acyl substitution reaction, the two steps must occur separately. It is a common mistake to draw these two steps as occurring together. 

The mechanism is believed to involve several steps. First, the Oi protons are removed and replaced with bromine atoms, one at a time. Then, the tribromomethyl group can function as a leaving group, resulting in a nucleophilic acyl substitution reaction. 

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