Substitution reactions at carbonyl group

We saw in Chapter 6 that the lone pairs of a carbonyl group may be proto-nated by acid. Only strong acids are powerful enough to protonate carbonyl groups the pKa of protonated acetone is -7, so, for example, even lM HC1 (pH 0) would protonate only 1 in 107 molecules of acetone. However, even proportions as low as this are sufficient to increase the rate of substitution reactions at carbonyl groups enormously, because those carbonyl groups that are protonated become extremely powerful electrophiles. 

Polyamides, polyesters, and polycarbonates are formed by substitution reactions at carbonyl groups... 

Numerous kinetic studies have confirmed that this mechanism, with a tetrahedral intermediate, is the normal pathway by which substitution reactions at carbonyl groups take place, as we explained in Chapter 10. You could draw a similar pathway, and a similar energy profile, for all of the reactions shown on p. 215, adjusting the energies of the starting materials, products, and intermediates appropriately, but all of them are second order, with rate-limiting attack on the carbonyl group. 

The carbonyl group is one of the most prevalent of the functional groups and is involved in many synthetically important reactions. Reactions involving carbonyl groups are also particularly important in biological processes. Most of the reactions of aldehydes, ketones, esters, carboxamides, and the other carboxylic acid derivatives directly involve the carbonyl group. We discussed properties of enols and enolates derived from carbonyl compounds in Chapter 6. In the present chapter, the primary topic is the mechanisms of addition, condensation and substitution reactions at carbonyl centers. We deal with the use of carbonyl compounds to form carbon-carbon bonds in synthesis in Chapters 1 and 2 of Part B. 

In many reactions at carbonyl groups, a key step is the addition of a nucleophile, which generates a tetracoordinate carbon atom. The overall course of the reaction is then determined by the fate of this tetrahedral intermediate. Addition occurs when the tetrahedral intermediate goes directly on to product. Condensation occurs if the carbonyl oxygen is eliminated and a double bond is formed. Substitution results when one of the groups is eliminated from the tetrahedral intermediate to re-form a carbonyl group. 

Chapters 1 and 2 dealt with formation of new carbon-carbon bonds by reactions in which one carbon acts as the nucleophile and another as the electrophile. In this chapter we turn our attention to noncarbon nucleophiles. Nucleophilic substitution is used in a variety of interconversions of functional groups. We discuss substitution at both sp3 carbon and carbonyl groups. Substitution at saturated carbon usually involves the Sjv2 mechanism, whereas substitution at carbonyl groups usually occurs by addition-elimination. 

It is useful to classify the more polar solvents (e > 15) into two categories depending on whether they are protic or aprotic. It is found that reactions involving bases, as for example SN2 substitutions (Chapter 4), E2 eliminations (Chapter 7), and substitutions at carbonyl groups (Chapter 8), proceed much faster in dipolar aprotic than in protic solvents, typically by factors of three to four powers of ten and sometimes by as much as six powers of ten.31... 

As you now appreciate, all substitution reactions at a carbonyl group go via a tetrahedral intermediate. 

Cr, Br, and 1 are good nucleophiles in substitution reactions at sp hybridized carbons, but they are ineffective nucleophiles in addition. Addition of Cl" to a carbonyl group, for example, would cleave the C—O 7i bond, forming an alkoxide. Because Cl" is a much weaker base than the alkoxide formed, equilibrium favors the starting materials (the weaker base. Cl"), not the addition product. 

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

Isatin is a stable, bright orange solid that is commercially available in large quantities. Because it readily undergoes clean aromatic substitution reactions at C-5, iV-alkylation via an anion, and ketonic reactions at the C-3-carbonyl group, for example enolate addition, it is a very useful intermediate for the synthesis of indoles and other heterocycles. 

Let us now examine how substituent effects in reactants influence the rates of nucleophilic additions to carbonyl groups. The most common mechanism for substitution reactions at carbon centers is by an addition-elimination mechanism. The adduct formed by the nucleophilic addition step is tetrahedral and has sp hybridization. This adduct may be the product (as in hydride reduction) or an intermediate (as in nucleophilic substitution). For carboxylic acid derivatives, all of the steps can be reversible, but often one direction will be strongly favored by product stability. The addition step can be acid-catalyzed or base-catalyzed or can occur without specific catalysis. In protic solvents, proton transfer reactions can be an integral part of the mechanism. Solvent molecules, the nucleophile, and the carbonyl compound can interact in a concerted addition reaction that includes proton transfer. The overall rate of reaction depends on the reactivity of the nucleophile and the position of the equilibria involving intermediates. We therefore have to consider how the substituent might affect the energy of the tetrahedral intermediate. 

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