Nucleophilic acyl substitution reactions tetrahedral intermediate

The reaction of ammonia and amines with esters follows the same general mechanistic course as other nucleophilic acyl substitutions. A tetrahedral intermediate is formed in the first stage of the process and dissociates in the second stage. 

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... 

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... 

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. 

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. 

The addition of a nucleophile to a polar C=0 bond is the key step in three of the four major carbonyl-group reactions. VVe saw in Chapter 19 that when c nucleophile adds to an aldehyde or ketone, the initially formed tetrahedral intermediate either can be protonated to yield an alcohol or can eliminate the carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to a carboxydic acid derivative, however, a different reaction course is followed. The initially formed tetrahedral intermediate eliminates one of the tw o substituents originally bonded to the carbonyl carbon, leading to a net nucleophilic acyl substitution reaction (Figure 21.1). 

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. 

Class I carbonyl compounds undergo nucleophilic acyl substitution reactions. These reactions are discussed in Chapter 17, where you will see that all Class I carbonyl compounds react with nucleophiles in the same way— they form an unstable tetrahedral intermediate that collapses by eliminating the weakest base. So all you need to know to determine the product of a reaction—or even whether a reaction will occur—is the relative basicity of the groups in the tetrahedral intermediate. 

We can make the following general statement about the reactions of carboxylic acid derivatives A carboxylic acid derivative will undergo a nucleophilic acyl substitution reaction, provided that the newly added group in the tetrahedral intermediate is not a much weaker base than the group that was attached to the acyl group in the reactant. 

We have just seen that there are two steps in a nucleophilic acyl substitution reaction formation of a tetrahedral intermediate and collapse of the tetrahedral intermediate. The weaker the base attached to the acyl group, the easier it is for both steps of the... 

A weak base attached to the acyl group will also make the second step of the nucleophilic acyl substitution reaction easier because weak bases are easier to eliminate when the tetrahedral intermediate collapses. 

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. 

All carboxylic acid derivatives undergo nucleophilic acyl substitution reactions by the same mechanism. If the nucleophile is negatively charged, the mechanism discussed in Section 17.5 is followed The nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. When the tetrahedral intermediate collapses, the weaker base is eliminated. 

What will be the product of a nucleophilic acyl substitution reaction—a new carboxylic acid derivative, a mixture of two carboxylic acid derivatives, or no reaction—if the new group in the tetrahedral intermediate is the following ... 

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 ... 

Figure21.1 The general mechanisms of nucleophilic addition and nucleophilic acyl substitution reactions. Both reactions begin with addition of a nucleophile to a polar C=0 bond to give a tetrahedral, alkoxide ion intermediate. (a) The intermediate formed from an aldehyde or ketone is protonated to give an alcohol, but (b) the intermediate formed from a carboxylic acid derivative expels a leaving group to give a new carbonyl compound.

The first step of the reaction is addition of the Grignard reagent to the carbonyl group to give a tetrahedral intermediate. It releases an alkoxide ion complexed with magnesium bromide. Thus, the reaction is a typical nucleophilic acyl substitution reaction. 

Methoxide functions as a base and deprotonates the most acidic position, leading to a doubly-stabilized enolate. This enolate then functions as a nucleophile and attacks the ester in an intramolecular nucleophilic acyl substitution reaction. The resulting tetrahedral intermediate loses methoxide to reform the carbonyl group. The OH... 

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