Aldehyde, Ketone, and Ester Enolates

It is convenient to use Greek letters to designate atoms in relation to the carbonyl group in an aldehyde, ketone, or ester. The carbon adjacent to the carbonyl carbon is the a carbon atom, the next one down the chain is the P carbon, and so on. Butanal, for example, has an a carbon, a (3 carbon, and a 7 carbon. 

Our experience to this point has been that C—H bonds are not very acidic. Alkanes, for example, have of approximately 60. Compared with them, however, aldehydes, ketones, and esters have relatively acidic hydrogens on their a-carbon atoms (Table 20.1). 

1 TABLE 20.1 p/Ca Values of Some Aldehydes, Ketones, and Esters  

Find the most acidic hydrogen in each of the following and write a chemical equation for the proton-transfer process that occurs on reaction with hydroxide ion. Use curved arrows to show electron flow and label the acid, base, conjugate acid, and conjugate base. 

Sample Solution (a) The only a hydrogens in ferf-butyl methyl ketone are those of the methyl group attached to the carbonyl. Only a hydrogens are acidic enough to be removed by hydroxide. None of the hydrogens of the ferf-butyl group are a hydrogens. 

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Aldehyde, Ketone, and Ester Enolates 867 Enolate Regiochemistry 872 The Aldol Condensation 873 Mixed Aldol Condensations 878 Chalcones From the Mulberry Tree to Cancer Chemotherapy 880 The Claisen Condensation 882 Intramolecular Claisen Condensation The Dieckmann Cyclization 884 Mixed Claisen Condensations 885 Acylation of Ketones with Esters 886 Alkylation of Enolates 887 The Acetoacetic Ester Synthesis 889 The Malonic Ester Synthesis 891 Alkylation of Chiral Enolates 893 Enolization and Enol Content 895 a Halogenation of Aldehydes and Ketones 900... 

Simple aldehyde, ketone, and ester enolates are relatively basic, and their alkylation is limited to methyl and primary alkyl halides secondary and tertiary alkyl halides undergo elimination. Even when alkylation is possible, other factors intervene that can reduce its effectiveness as a synthetic tool. It is not always possible to limit the reaction to monoalkylation, and aldol addition can compete with alkylation. With unsymmetrical ketones, regioselectivity becomes a consideration. We saw in Section 20.2 that a strong, hindered base such as lithium diisopropylamide (LDA) exhibits a preference for abstracting a proton from the less-substituted a carbon of 2-methylcyclohexanone to form the kinetic enolate. Even under these conditions, however, regioisomeric products are formed on alkylation with benzyl bromide. 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Enolates of aldehydes, ketones, and esters and the carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized carbanions and ylides, undergo the reaction. The synthetic applications of this group of reactions will be discussed in detail in Chapter 2 of Part B. In this section, we will discuss the fundamental mechanistic aspects of the reaction of ketone enolates with aldehydes md ketones. 

We shall need to understand the formation of enol(ate)s from aldehydes, ketones and esters and it is worthwhile establishing now that these three types of compounds form a graded series of electrophiles whilst their enolates form a graded series of nucleophiles in the reverse direction. Any of these enolates can react with any of the carbonyl compounds. 

The conjugated ylides derived from aldehydes, ketones, and esters are all sufficiently stable to be commercially available as the ylids—one of the few examples of specific enol equivalents that you can actually buy. The ylid corresponding to the enolate of acetaldehyde is a solid, m.p. 185-188 °C that reacts well with other aldehydes, even if they are enolizable. 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

Enols, too, show both O—H and C O absorption these can be distinguished by the particular frequency of the C= 0 band. Aldehydes, ketones, and esters show carbonyl absorption, but the O—H band is missing. (For a comparison of certain oxygen compounds, see Table 20.3, p. 689.)... 

The different methods available for doing aldol reactions with enolates of aldehydes, ketones, and esters... 

These tri(alkoxy)titanium enolates, which have low Lewis acidity, are known to react chemoselective-ly with an aldehyde group in the presence of a ketone (equation 4). Other uses described by Reetz et al. include the diastereofacially selective additions of ketone and ester enolates to chiral a-alkoxy aldehydes with nonchelation control. - For example, aldol addition of the tri(isopropoxy)titanium enolate of pro-piophenone to the aldehyde (24) leads to only the two syn diastereomers, with the nonchelation adduct (25) favored (equation 5) i.e. Felkin-Anh selectivity is operating. In the case of aldol addition of t-butyl propionate to the same aldehyde (equation 6), highest stereoselectivity for the isomer (26) is obtained using the tri(diethylamino)titanium enolate. Very high levels of nonchelation stereoselectivity can also be obtained in the aldol addition to chiral a-siloxy or a-benzyloxy ketones if a titanium enolate of low Lewis acidity is employed, as in equation (7). ... 

Aldehydes, ketones, and esters can be converted to their enolate anions by treatment with a metal alkoxide or other strong base. 

This chapter will discuss carbanion-like reactions that utilize enolate anions. The acid-base reactions used to form enolate anions will be discussed. Formation of enolate anions from aldehyde, ketones, and esters will lead to substitution reactions, acyl addition reactions, and acyl substitution reactions. Several classical named reactions that arise from these three fundamental reactions of enolate anions are presented. In addition, phosphonium salts wiU be prepared from alkyl halides and converted to ylids, which react with aldehydes or ketones to form alkenes. These ylids are treated as phosphorus-stabilized car-banions in terms of their reactivity. 

One molar equivalent of LDA converts aldehydes, ketones, and esters completely to their enolate anions. 

Although it is mechanistically different from the Tsuji-Trost allylation, indirect allyla-tions of ketones, aldehydes, and esters via their enolates are briefly summarized here. Related reactions are treated in Sect V.2.1.4. Pd-catalyzed allylation of aldehydes, ketones, and esters with aUyhc carbonates is possible via the Tr-allylpaUadium enolates of these carbonyl compounds. Tr-AUylpalladium enolates can be generated by the treatment of silyl and stannyl enol ethers of carbonyl compounds with allyl carbonates, and the allylated products are obtained by the reductive elimination of the Tr-allylpalladium enolates. 

You learned in Chapter 17 that nucleophilic addition to aldehydes and ketones is one of the fundamental reaction types of organic chemistry, then in Chapter 19 you saw that addition to carbonyl groups in carboxylic acid derivatives can lead to nucleophilic acyl substitution. In this chapter, you ll encounter a third pattern of carbonyl reactivity—one that involves the enol tautomers of aldehydes, ketones, and esters and the conjugate bases of enols known as enolates. 

Section 20.1 Aldehydes, ketones, and esters having at least one a hydrogen exist in equilibrium with their enols. The enol content of simple aldehydes, ketones, and esters is small. 

Aldehydes, ketones and esters of general formula 708 reacted with amidines to give pyrimidine derivatives (Table 40, Entries 1-4). Analogous methods were developed for (per)fluorinated vinyl halides 709 (Entry 5) and 710 (Entries 6, 7). Analogous reaction was successful with enol phosphate 814, obtained from ketone 813 and sodium diethyl phosphite (Scheme 162) [120], In aU these cases, nucleophilic substitution of two fluorine atoms at a-carbon of the perfluoroalkyl group occurred. 

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