Reactions of Carbonyl Compounds

Carbonyl compounds comprise a large and important class of organic substances, and the chemistry of this functional group is essential to the understanding of many chemical and biochemical processes.1 In this chapter we use a few fundamental ideas of mechanism to correlate reactions of various carbonyl functional groups. We shall touch briefly on the closely related chemistry of carbon-nitrogen double bonds. 

Carbonyl reactions may be understood in terms of two basic processes addition of a nucleophile to the carbonyl carbon (Equation 8.1) and removal of a proton from the carbon adjacent to the carbonyl group (Equation 8.2). In the first process the carbonyl molecule is acting as a Lewis acid, and in the second 

1 Reviews of various aspects of carbonyl chemistry may be found in the following sources (a) W. P. Jencks, Catalysis in Chemistry and Enzymology, McGraw-Hill, New York, 1969 (b) W. P. Jencks, Prog. Phys. Org. Chem., 2, 63 (1964) (c) R. P. Bell, Adoan. Phys. Org. Chem., 4, 1 (1966) (d) S. Patai, Ed., The Chemistry of the Carbonyl Group, Vol. 1, and J. Zabicky, Ed., The Chemistry of the Carbonyl Group, Vol. 2, Wiley-Interscience, London, 1966 and 1970 (e) S. Patai, Ed., The Chemistry of Acyl Halides, Wiley-Interscience, London, 1972. 

Resonance stabilization of the anion formed from a (3-dicarbonyl compound. 

The term condensation refers to the joining of two molecules with the splitting out of a smaller molecule. The Claisen condensation is used extensively in the synthesis of dicarbonyl compounds. In biochemistry it is used to build fatty acids in the body. The Dieckmann condensation, the crossed Claisen condensation, and others (with other carbanions) cire variations of the Claisen condensation. In this section we briefly look at these variations. 

The Claisen condensation is one method of synthesizing (3-dicarbonyl compounds, specifically a (3-keto ester. This reaction begins with an ester and occurs in two steps. In the first step, a strong base, such as sodium ethoxide, removes a hydrogen ion from the carbon atom adjacent to the carbonyl group in the ester. (Resonance stabilizes the anion formed from the ester.) The anion can then attack a second molecule of the ester, which begins a series of mechanistic steps until the anion of the (3-dicarbonyl compound forms, which, in the second reaction step (acidification), gives the product. 

The Claisen condensation bears some resemblance to the Aldol condensation seen in Chapter 11. The initial step in the mechanisms are very similar in that in both cases a resonance-stabilized ion is formed. 

The use of sodium ethoxide for a Claisen condensation-type reaction. 

In many reactions at carbonyl groups, a key step is addition of a nucleophile, generating a tetracoordinate carbon atom. The overall course of the reaction is then determined ly the fate of this tetrahedral intermediate. 

The reactions of the specific classes of carbonyl compounds are related by the decisive importance of tetrahedral intermediates, and differences in reactivity can often be traced to structural features present in the tetrahedral intermediates. 

FIGURE 23.6 Lewis acid-catalyzed reactions of aromatic compounds. 

FIGURE 23.7 Coordination of oxygen to a Lewis and a Br0nsted acid. 

FIGURE 23.8 Lewis acid catalysis of simple carbonyl transformations. 

FIGURE 23.10 Exampies ofthe Mukaiyama aidoi condensation. 

FIGURE 23.11 Conjugate additions catalyzed by Lewis acids. 

The n bonding orbital is polarized toward the oxygen atom. The results of an SHMO calculation yield n = 0.540(2/ , ) + 0.841 [2pq). Thus the smaller coefficient of the carbon 2p orbital means that the carbonyl n bond will interact rather weakly with substituents attached to the carbon atom. The energy of the HOMO, = a — 1.651 jl, suggests that 

Simple orbital interaction theory is only partially infonnative in distinguishing the relative basicities (nucleophilicities) of carbonyl groups in different bonding environments, 

Basicity in the gas phase is measured by the proton affinity (PA) of the electron donor and in solution by the pATb. A solution basicity scale for aldehydes and ketones based on hydrogen bond acceptor ability has also been established [186]. Nucleophilicity could be measured in a similar manner, in the gas phase by the affinity for a particular Lewis acid (e.g., BF3) and in solution by the equilibrium constant for the complexation reaction. In Table 8.1 are collected the available data for a number of oxygen systems. It is clear from the data in Table 8.1 that the basicities of ethers and carbonyl compounds, as measured by PA and pA), are similar. However, the nucleophilicity, as measured by the BF3 affinity, of ethers is greater than that of carbonyl compounds, the latter values being depressed by steric interactions. 

TABLE 8.1. Ionization Potentials (IP), Proton Affinities (PA), piTb Valnes, anti BF3 Affinities 

Part IV Advanced Topics (Every Student s Nightmare) 

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The second property of a carbonyl moiety is to increase the acidity of the a-hydrogen atoms, which are those on the carbon atoms directly attached to the carbonyl carbon atom. A result of the enhanced acidity of these a-hydrogens is that the a-carbon atoms can become nucleophilic either through deprotonation to form an enolate ion (Eq. 18.3), or by a keto-enol equilibration, called tau-tomerization, to give an enol (Eq. 18.4). As shown in Equation 18.3, an enolate, which is the resonance hybrid of the two contributing resonance structures 2a and 2b, can react with electrophiles, E, at an a-carbon atom to give net substitution of the electrophile for an a-hydrogen atom. A similar result attends the reaction of an enol 3 with an electrophile, E+ (Eq. 18.4). 

Introduction As noted in the preceding section, the ability of the carbonyl group to increase the 

The Homer-Wadsworth-Emmons reaction is an important variant of the Wittig reaction and involves using a phosphonate ester in place of a phosphonium salt. Like the phase-transfer Wittig reaction just discussed, these reactions may be easily performed in the undergraduate laboratory. In one of the procedures that follows, the phosphonate ester 12 is deprotonated with potassium tert-butoxide in the polar, aprotic solvent N,N-dimethylformamide, (CH3)2NCHO (DMF), to provide the resonance-stabilized, nucleophilic phosphonate anion 13 (Eq. 18.7). 

By obtaining spectral data for your product, you will be able to determine which of the stilbenes is produced. An explanation of why the Wadsworth-Emmons reaction mainly yields a single diastereomer of stilbene is beyond the scope of this discussion. 

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Based on a general knowledge of base-catalyzed reactions of carbonyl compounds, a reasonable sequence of steps can be written, but the relative rates of the steps is an open question. Furthermore, it is known that reactions of this type are generally reversible so that the potential reversibility of each step must be taken into account. A completely... 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

The mechanistic pattern established by study of hydration and alcohol addition reactions of ketones and aldehydes is followed in a number of other reactions of carbonyl compounds. Reactions at carbonyl centers usually involve a series of addition and elimination steps proceeding through tetrahedral intermediates. These steps can be either acid-catalyzed or base-catalyzed. The rate and products of the reaction are determined by the reactivity of these tetrahedral intermediates. 

As is clear from the preceding examples, there are a variety of overall reactions that can be initiated by photolysis of ketones. The course of photochemical reactions of ketones is veiy dependent on the structure of the reactant. Despite the variety of overall processes that can be observed, the number of individual steps involved is limited. For ketones, the most important are inter- and intramolecular hydrogen abstraction, cleavage a to the carbonyl group, and substituent migration to the -carbon atom of a,/S-unsaturated ketones. Reexamination of the mechanisms illustrated in this section will reveal that most of the reactions of carbonyl compounds that have been described involve combinations of these fundamental processes. The final products usually result from rebonding of reactive intermediates generated by these steps. 

Reaction of Carbonyl Compounds with Sulfur Tetrafluoride... 

Participation of fluorocarbocations, derived from carboxylic acids and from halo acetones, in reactions of carbonyl compounds with sulfur tetrafluoride has been directly evidenced by trapping them with aromatic hydrocarbons [207, 20S],... 

In similar work, CF3CCI2CO2CH3 yields methyl a-trifluoromethyl-a,(i-un-saturated carboxylates when reacted with a zinc-copper couple, aldehydes, and acetic anhydride [67] (equation 55). This methodology gives (Z)-a-fluoro-a- -un-saturated carboxylates from the reaction of carbonyl compounds with CFCI2CO2CH3 and zinc and acetic anhydride [6 ]. 

Catalytic enantioselective hetero-Diels-Alder reactions are covered by the editors of the book. Chapter 4 is devoted to the development of hetero-Diels-Alder reactions of carbonyl compounds and activated carbonyl compounds catalyzed by many different chiral Lewis acids and Chapter 5 deals with the corresponding development of catalytic enantioselective aza-Diels-Alder reactions. Compared with carbo-Diels-Alder reactions, which have been known for more than a decade, the field of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds and imines (aza-Diels-Alder reactions) are very recent. 

Catalytic Enantioselective Cycloaddition Reactions of Carbonyl Compounds... 

This chapter will focus on the development of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes (Scheme 4.1) [3]. 

The main strategy for catalytic enantioselective cycloaddition reactions of carbonyl compounds is the use of a chiral Lewis acid catalyst. This approach is probably the most efficient and economic way to effect an enantioselective reaction, because it allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires a sub-stoichiometric amount of chiral material. 

To achieve catalytic enantioselective cycloaddition reactions of carbonyl compounds, coordination of a chiral Lewis acid to the carbonyl functionality is necessary. This coordination activates the substrate and provides the chiral environment that forces the approach of a diene to the substrate from the less sterically hindered face, introducing enantioselectivity into the reaction. 

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