Tetrahedral carbonyl compounds, nucleophilic

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... 

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. 

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 factors involved in the attack of nitrogen nucleophiles on carbonyl compounds, e.g. the p/fa of the nitrogen, and the thermodynamics of the formation of neutral (T ) versus zwitterionic (T ) tetrahedral intermediates, have been discussed in terms of their influence on the form of the pH-rate profile. ... 

Figure 3-1. The formation of a tetrahedral intermediate in the reaction of a nucleophile with a carbonyl compound.

We showed in Figs. 3-2 and 3-3 that the tetrahedral intermediate which is initially formed from the reaction of a nucleophile with a carbonyl compound may further react in a number of different ways. In this section, we will consider some reactions which proceed along the pathway indicated in Fig. 3-3. The hydration of ketones is a reaction analogous to the hydrolysis of an ester, with the first step of the reaction involving nucleophilic attack of water on the carbonyl group. The tetrahedral intermediate is trapped by reaction with a proton to yield the hydrated form of the ketone, the geminal diol (Fig. 3-15). Similar reactions occur with alcohols as nucleophiles to yield, initially, hemiacetals. 

At the beginning of this chapter we considered the ways in which co-ordination to a metal ion might control the reactions of a carbonyl compound. We considered the possible fates of the tetrahedral intermediate formed by the attack of a nucleophile upon the carbonyl carbon atom. In the case of a nucleophile such as ammonia or a primary amine another pathway leading to an imine is open. 

The SN reaction under consideration is not terminated until water, a dilute acid, or a dilute base is added to the crude reaction mixture. The tetrahedral intermediate B is then protonated to give the compound E. Through an El elimination it liberates the carbonyl compound C (cf. discussion of Figure 6.4). Fortunately, at this point in time no overreaction of this aldehyde with the nucleophile can take place because the nucleophile has been destroyed during the aqueous workup by protonation or hydrolysis. In Figure 6.32 this process for chemoselective acylation of hydride donors, organometallic compounds, and heteroatom-stabilized carbanions has been included as strategy 1. ... 

For a given nucleophile the equilibrium lies farther on the product side the smaller the substituents R1 and R2 of the carbonyl compound are (Figure 7.7). Large substituents R1 and R2 prevent the formation of addition products. This is because they come closer to each other in the addition product, where the bonds to R1 and R2 enclose a tetrahedral angle, than in the carbonyl compound, where these substituents are separated... 

The strength of the nucleophile and the structure of the carbonyl compound determine whether the equilibrium lies on the side of the carbonyl compound or the tetrahedral adduct. Water, a weak nucleophile, does not usually add to the carbonyl group to form a stable compound ... 

It is, of course, the carbonyl group that makes acyl compounds more reactive than alkyl compounds. Nucleophilic attack (Sn2) on a tetrahedral alkyl carbon involves a badly crowded transition state containing pentavalent carbon a bond must be partly broken to permit the attachment of the nucleophile ... 

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