Substitution reactions at carbonyl

Table 19.2 Nucleophilic Substitution Reactions at Carbonyl Carbons...

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... 

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. 

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 analogy between imines and carbonyls was introduced earlier, and just as 1,3-dike-tonate complexes undergo electrophilic substitution reactions at the 2-position, so do their nitrogen analogues. Reactions of this type are commonly observed in macrocyclic ligands, and many examples are known. Electrophilic reactions ranging from nitration and Friedel-Crafts acylation to Michael addition have been described. Reactions of 1,3-diimi-nes and of 3-iminoketones are well known. The reactions are useful for the synthesis of derivatised macrocyclic complexes, as in the preparation of the nickel(n) complex of a nitro-substituted ligand depicted in Fig. 5-12. 

Base-catalyzed hydration of conjugated carbonyls, followed by retro-aldol fragmentation has been a common strategy for studying the reaction cascade (1-4). The kinetically important step in the base-catalyzed hydration of an alpha/beta unsaturated carbonyl is similar to a nucleophilic substitution reaction at carbon 3. The reaction cascade proceeds rapidly from the conjugated carbonyl through its hydration and subsequent fragmentation. 

Tetrahedral intermediate (Section 18.1) The intermediate formed in a substitution reaction at a carbonyl carbon, in which a nucleophile bonds to the carbonyl carbon, resulting in the formation of an. -hybridized carbon in the intermediate. 

Considering these heats of deprotonation, one wonders whether organolithium compounds should not be at least as suitable as lithium amides for effecting the deprotonation of carbonyl and carboxyl compounds. However, this is usually not the case, since organolithium compounds react almost always as nucleophiles rather than as bases. Organolithium compounds thus would add to the carbonyl carbon (Section 8.5) or engage in a substitution reaction at the carboxyl carbon (Section 6.5). 

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

Co-polymerization of pentaerythritol and two other monomers—an unsaturated acid and benzene 1,3-dicarboxylic acid—gives a network of polymer chains branching out from the quaternary carbon atom at the centre of pentaerythritol. The reaction is simply ester formation by a carbonyl substitution reaction at high temperature (> 200°C). Ester formation between acids and alcohols is an equilibrium reaction but at high temperatures water is lost as steam and the equilibrium is driven over to the right. 

The use of carbonylate anions as nucleophiles in substitution reactions at metals has been used for a long time to prepare other Re-M metal-bonded derivatives, for example, ReCo(CO)9 from [Re(CO)6]+ and [Co(CO)4] and (168) from [ReBr(CO)4]2 and [Fe(C0)4 C(0)R ][NMe4]. ... 

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. 

Chapter 23 concentrates on substitution reactions at the a carbon, whereas Chapter 24 concentrates on reactions between two carbonyl compounds, one of which serves as the nucleophile and one of which is the electrophile. Many of the reactions in Chapter 23 form new carbon-carbon bonds, thus adding to your repertoire of reactions that can be used to synthesize more complex organic molecules from simple precursors. As you will see, the reactions introduced in Chapter 23 have been u.sed to prepare a wide variety of interesting and useful compounds. 

Chapter 23 Substitution Reactions of Carbonyl Compounds at the a Carbon... 

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