Nucleophilic carbonyl addition reaction kinds

We are in a strange, complex chemical environment here, but in it we recognize familiar kinds of compounds—hemiacetals, esters, anhydrides, carboxylic acids—and familiar kinds of reactions—nucleophilic carbonyl addition, hydride transfer, nucleophilic acyl substitution. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

It has been found that amines frequently are effective catalysts for addition of other nucleophiles to carbonyl groups.108 The reason for this catalysis is that amines can add rapidly to the carbonyl compound to form an imine the imine in turn is subject to the same kinds, of addition reactions as are carbonyl compounds, but reacts faster because it is more easily protonated. Scheme 16 illus-... 

Most reactions of carbonyl groups occur by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, am carbonyl condensation. These mechanisms have many variations, just a alkene electrophilic addition reactions and 8 2 reactions do, but the varia tions are much easier to learn when the fundamental features of the mechanisms are understood. Let s see what the four mechanisms are and what kinds of chemistry carbonyl groups undergo. 

The most important kinds of conjugate addition reactions are Michael reactions, which involve the addition of C nucleophiles to C=C 7r bonds. The nucleophiles are often 1,3-dicarbonyl compounds such as malonates, cyanoacetates, j8-ketoesters, and 1,3-diketones, but simple carbonyl compounds may also be used. Only catalytic amounts of base are usually required. 

Stereoselective Nucleophilic Additions to Acyclic Carbonyl Groups The stereochemistry of nucleophilic addition to acyclic aldehydes and ketones is influenced by nearby substituents. A particularly important case occurs when there is a stereogenic center adjacent to the carbonyl group. As a result of the adjacent substituent, two diastereomers can be formed, depending on the direction of the approach of the nucleophile. The stereoselectivity of addition can be predicted on the basis of a conformational model of the TS. The addition reaction has been studied with several kinds... 

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... 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an ,j6-unsaturated carbonyl compound—a process known as the Michael reaction. 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

What kind of reagents will attack such a group Since the important step in these reactions is the formation of a bond to the electron-deficient (acidic) carbonyl carbon, the carbonyl group is most susceptible to attack by electron-rich, nucleophilic reagents, that is, by basesi The typical reaction of aldehydes and ketones is nucleophilic addition. 

Nature uses the two-carbon acetate fragment of acetyd CoA as the major building block for synthesis. Acetyl CoA can act not only as an electrophilic acceptor, being attacked by nucleophiles at the carbonyl group, but also as a nucleophilic donor by loss of its acidic a hydrogen. Once formed, the enolate ion of acetyl CoA can add to another carbonyl group in a condensation reaction. For example, citric acid is biosynthesized by nucleophilic addition of acetyl CoA to the ketone carbonyl group of oxaloacetic acid (2-oxob i-tanedioic acid) in a kind of mixed aldol reaction. 

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