Carbonyl addition reactions tetrahedral intermediate

In general terms, there are three possible mechanisms for addition of a nucleophile and a proton to give a tetrahedral intermediate in a carbonyl addition reaction. 

The transformation of2-734 involves an initial generation of an organosamarium species 2-735 with subsequent nucleophilic addition to the lactone carbonyl. Presumably, a tetrahedral intermediate 2-736 is formed that collapses to yield the ketone 2-737. This reacts with Sml2 to give a ketyl radical 2-738, which undergoes an intramolecular S-exo radical cyclization reaction with the alkene moiety. The resultant... 

In the Claisen condensation, a nucleophilic ester enolate donor is added to the carbonyl group of a second ester molecule. Loss of alkoxide from the resultant intermediate — the tetrahedral adduct — forms a P-keto ester, which is much more acidic than the starting ester. Hence, deprotonation of the initial product by alkoxide drives the overall reaction to completion and protects the P-keto ester from further carbonyl addition reactions. Thus, the starting ester must have at least two a-hydrogens. 

There are carbonyl addition reactions that are examples of each of the general mechanisms, and a two-dimensional potential energy diagram provides a useful framework within which to consider specific addition reactions. The breakdown of a tetrahedral intermediate involves the same processes but operates in the opposite direction, so the principles that are developed also apply to the reactions of the tetrahedral intermediates. Let us examine the three general mechanistic cases in relation to the energy diagram in Figure 7.1. 

This mixed anhydride then undergoes a carbonyl addition reaction with the sulfhydryl group of coenzyme A to form a tetrahedral carbonyl addition intermediate, which collapses to give AMP and an acyl-CoA (a fatty acid thioester of coenzyme A) ... 

All these reactions proceed by nucleophilic addition of the amine to the carbonyl group Dissociation of the tetrahedral intermediate proceeds m the direction that leads to an amide... 

In many reactions at carbonyl groups, a key step is addition of a nucleophile, generating a tetracoordinate carbon atom. The overall course of the reaction is then determined ly the fate of this tetrahedral intermediate. 

The mechanistic pattern established by study of hydration and alcohol addition reactions of ketones and aldehydes is followed in a number of other reactions of carbonyl compounds. Reactions at carbonyl centers usually involve a series of addition and elimination steps proceeding through tetrahedral intermediates. These steps can be either acid-catalyzed or base-catalyzed. The rate and products of the reaction are determined by the reactivity of these tetrahedral intermediates. 

The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution ... 

When written in this way it is clear what is happening. The mechanisms of these reactions are probably similar, despite the different p values. The distinction is that in Reaction 10 the substituent X is on the substrate, its usual location but in Reaction 15 the substituent changes have been made on the reagent. Thus, electron-withdrawing substituents on the benzoyl chloride render the carbonyl carbon more positive and more susceptible to nucleophilic attack, whereas electron-donating substituents on the aniline increase the electron density on nitrogen, also facilitating nucleophilic attack. The mechanism may be an addition-elimination via a tetrahedral intermediate ... 

As we saw in A Preview of Carbonyl Compounds, the most general reaction of aldehydes and ketones is the nucleophilic addition reaction. A nucleophile, Nu-, approaches along the C=0 bond from an angle of about 75° to the plane of the carbonyl group and adds to the electrophilic C=0 carbon atom. At the same time, rehybridization of the carbonyl carbon from sp2 to sp3 occurs, an electron pair from the C=0 bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced (Figure 19.1). 

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... 

The addition of a nucleophile to a polar C=0 bond is the key step in thre< of the four major carbonyl-group reactions. We saw in Chapter 19 that when. nucleophile adds to an aldehyde or ketone, the initially formed tetrahedra intermediate either can be protonated to yield an alcohol or can eliminate th< carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to carboxylic acid derivative, however, a different reaction course is followed. Tin initially formed tetrahedral intermediate eliminates one of the two substituent originally bonded to the carbonyl carbon, leading to a net nucleophilic acy substitution reaction (Figure 21.1. ... 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The importance of displacement reactions on carbonyl compounds in chemistry and biochemistry has resulted in numerous mechanistic studies. In solution, there is general acceptance of the following mechanism for addition of anionic nucleophiles which features a tetrahedral intermediate, 1, and is designated (1). However, recent experimental (2 10) and theoretical (11-17)... 

The reactions that are discussed in this section involve addition of carbon nucleophiles to carbonyl centers having a potential leaving group. The tetrahedral intermediate formed in the addition step reacts by expulsion of the leaving group. The overall... 

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