Aldehydes and Ketones — Nucleophilic Addition

Figure 19.14 Carboxylic acid derivatives have an electronegative substituent Y = -Br, —Cl, -OR, -NR2 that can be expelled as a leaving group from the tetrahedral intermediate formed by nucleophilic addition. Aldehydes and ketones have no such leaving group and thus do not usually undergo this reaction.

In addition to nucleophilic additions, aldehydes and ketones show an unusual acidity of hydrogen atoms attached to carbons alpha (adjacent) to the carbonyl group. These hydrogens are referred to as a hydrogens, and the carbon to which they are bonded is an a carbon. In ethanal, there is one a carbon and three a hydrogens, while in acetone there are two a carbons and six a hydrogens. 

The nucleophilic addition reaction is the most common general reaction type for aldehydes and ketones. Many different kinds of products can be prepared by nucleophilic additions. Aldehydes and ketones are reduced by NaBH4 or UAIH4 to yield primary and secondary alcohols, respectively. Addition of Grignard reagents to aldehydes and ketones also gives alcohols (secondary and tertiary, respectively), and addition of HCN delds cyanohydrins. Primary amines add to carbonyl compounds yielding imines, or Schiff bases, and secondary... 

The addition of RLi and other nucleophiles to carbonyl functions in general proceeds via one of the two possible reaction pathways, polar addition (PL) and electron transfer (ET)-radical coupling (RC) sequence (equation 5). Current reaction design for the synthetic purpose of additions of common nucleophiles to aldehydes and ketones is mostly based on the polar mechanism, but apparently the ET process is involved in some reactions of, for example, Grignard reagents Mechanistically there are three possible variations the PL pathway, the ET rate-determining ET-RC route and the RC rate-determining ET-RC route. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

G. Solladie (1983). Addition of chiral nucleophiles to aldehydes and ketones , in Asymmetric Synthesis. Ed. J. D. Morrison. Orlando, Florida Academic Press, Vol. 2A, p. 157. 

Aldehydes and ketones react with alcohols to form hemiacetols and hemiketah, respectively. In this reaction the alcohols react in typical fashion as the nucleophile. When aldehydes and ketones are attacked by a nucleophile, they undergo addition. Aldehydes and hemiacetals, and ketones and hemiketals, exist in equilibrium when an aldehyde or ketone is dissolved in an alcohol however, usually the hemiacetal or hemiketal is too unstable to isolate unless if exists as a ring structure. If a second molar equivalent of alcohol is added, an oceiuf is formed from a hemiacetal, or a ketal is formed from a hemiketal. 

In all of the reactions with carboxylic acid derivatives, the carbonyl carbon is acting as the substrate in nucleophilic substitution. Rather than memorize all these reactions, you should remember that carboxylic acids and their derivatives undergo nucleophilic substitution aldehydes and ketones prefer nucleophilic addition. 

Predicting the Products of the Addition of Nucleophiles to Aldehydes and Ketones... 

The addition of sulfur nucleophiles to aldehydes and ketones may be exemplified by the formation of hydrogensulfite (bisulfite) adducts (3.12). These are sulfonates that are water soluble. However, their stcric bulk means that whereas they are formed from aldehydes and methyl ketones, more highly substituted ketones are reluctant to form these derivatives. 

A number of reactions of nitrogen-containing nucleophiles with aldehydes and ketones involve addition of the nitrogen to the carbon of the carbonyl group, followed by elimination of water to produce a double bond. Common examples are reactions of primary amines to produce substituted imines, reactions of secondary amines to produce enamines, reactions of hydrazine or substituted hydrazines to produce hydrazones, reactions of semicarbazides to give semicarbazones, and reactions of hydroxylamine to produce oximes. Usually these reactions are run with an acid catalyst. 

Computational results generally support the notion of nonperpendicular approach in additions of anionic nucleophiles to aldehydes and ketones. This finding, however, has to be qualified in two ways. First, the extent of deviation from the perpendicular approach direction clearly depends on the flexibility of the basis set it is very large with the minimal and small split-valence basis sets, known to exaggerate anisotropy of the charge distribution and thereby contributions of the coulombic interactions. Second, available information concerning the effects of Lewis acid catalysis, solvation and dielectric medium on the transition structures, suggests that the... 

Addition-elimination reactions may be carried out under either basic or acidic conditions. We have seen how additions of nucleophiles to aldehydes and ketones (Sections 17-5 through 17-9 Table 17-4) may be catalyzed by either bases or acids. The same is true for additions of nucleophiles to carboxylic acid derivatives. Eliminations from the tetrahedral intermediate are similarly catalyzed Recall that this process is mechanistically just the reverse of addition therefore, the same catalytic effects are observed. Let us examine the roles of both base and acid in detail. 

The additions of nucleophiles to aldehydes and ketones are promoted by coordination of a Lewis acid to the oxygen atom of the carbonyl group. The coordination with the metal enhances the electrophilicity of the C=0 group facilitating the attack of the nucleophile. From a stereochemical point of view, the presence of a Lewis acid is particularly important when a substituent with a heteroatom able to coordinate with the metal is placed next to the carbonyl group. In such cases, the prediction of the stereoselectivity of the reaction requires a chelated reactive conformation as that represented in Figure 4.2. This model is known as Cram s cyclic model and again the attack of flie nucleophile takes place preferentially from the less-hindered side. 

Aldehydes and Ketones Nucleophilic Addition to the Carbonyl Group... 

ALDEHYDES AND KETONES NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP... 

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