Carboxyl compounds enolates

Another important part of Organic 11 is carbonyl chemistry. We look at the basics of the carbonyls in Chapter 9. It s like a family reunion where 1 (John, one of your authors) grew up in North Carolina — everybody is related. You meet aldehydes, ketones, carboxylic acids, acyl chlorides, esters, cimides, and on and on. It s a quick peek, because later we go back and examine many of these in detail. For example, in Chapter 10 you study aldehydes and ketones, along with some of the amines, while in Chapter 11 we introduce you to other carbonyl compounds, enols and enolates, along with nitroalkanes and nitriles. 

Nucleophiles can be added to acceptor-substituted alkenes. In that case, enolates and other stabilized carbanions occur as intermediates. Reactions of this type are discussed in this book only in connection with 1,4-additions of organometallic compounds (Section 10.6), or enolates (Section 13.6) to a,/J-unsaturated carbonyl and carboxyl compounds. 

Certain alkylaryl selenides can be prepared by the electrophilic selenylation of enolates (Figure 4.12 also see Table 13.5). With a subsequent H202 oxidation to produce the selenox-ide followed by the elimination of Ph—Se—OH, one proceeds in a total of two synthetic steps from a carbonyl or carboxyl compound to its a,/J-unsaturated analogue. 

In the present—and next—chapter, the focus will once more be on the chemistry of molecules containing C=0 double bonds. However, Chapters 12 and 13 will for the first time deal with reactions taking place in the position next to the carbonyl or carboxyl group. They are known for both neutral derivatives of carbonyl or carboxyl compounds (Chapter 12) and their conjugate bases, i.e., the enolates (Chapter 13). The neutral derivatives of carbonyl or carboxyl compounds, that allow for reactions next to the C=0 double bond, are presented in the following scheme ... 

Carboxonium ions resulting from the electrophilic reaction on an enol are deprotonated at the O atom in the second reaction step. In this way an a-functionalized carbonyl or carboxyl compound is formed. This amounts to a two-step mechanism, but as far as experimental work is concerned it involves only a single-step electrophilic substitution next to the C=0 double bond of a carbonyl or carboxyl compound. In Section 12.2, this type of reaction is illustrated with numerous examples. 

Keto-Enol Tautomerism End Content of Carbonyl and Carboxyl Compounds... 

Carboxonium/oxocarbenium ions that are produced from a silyl enol ether or a silylketene acetal and an electrophile are desilylated in the second step of the reaction. This also produces an a-functionalized carbonyl or carboxyl compound. 

The electrophilic functionalization of carbonyl and carboxyl compounds next to the C=0 double bond generally proceeds in a single step via an SE reaction of the enol tautomer. The identification of suitable substrates for this type of reaction requires rough knowledge of the extent to which the respective enolization occurs. The enolization equilibrium constants KE or their —more easy-to-handle—negative logarithm values, the so-called pXE values, provide a quantitative measure thereof. These measures are defined as follows ... 

If a carbonyl or carboxyl compound that is capable of enolization, is to undergo complete reaction with an electrophile via its enol tautomer, it must be ensured that the latter is constantly resupplied from the carbonyl or carboxyl tautomer under the reaction conditions. If the tautomerization, which this process requires, occurs faster than the further reaction of the enol, the enol will be continuously available for the electrophile to react to completion—and always at the respective equilibrium concentration. But if the tautomerization is the slower reaction of the two, the enol will be depleted to less than its equilibrium concentration in the extreme case, it may even be totally consumed, and it will take some time before new enol will have formed. 

If the reaction between the enol and the electrophile proceeds extremely fast, the enol tautomer of a carbonyl or carboxyl compound might be consumed completely. The generation of enol becomes the rate-determining step. This situation occurs with the enol titration of ace-toacetic ester, (Figure 12.4). In this process, bromine is added to an equilibrium mixture of the ketone form (B) and the enol form (iso-B) of an acetoacetic ester. Bromine functionalizes the enol form via the intermediacy of the carboxonium ion E to form the bromoacetic ester D. The trick of conducting the enol titration is to capture the enol portion of a known amount of acetoacetic ester by adding exactly the equivalent amount of bromine. From the values for... 

QT-Fimctionalizat ion of Carbonyl and Carboxyl Compounds via Tautomeric Enols... 

Figure 12.13 shows that the iso-A enols of the /3-diketones A react with an a,/3-unsaturated carboxonium ion C that acts as a C electrophile. This oxocarbenium ion is formed by reversible protonation of the oc,/3-unsaturated methyl vinyl ketone in acetic acid. However, the oxocarbenium ion C in this figure does not react with the iso-A enols at its carbonyl carbon atom—as the protonated acetone in Figure 12.12 does with the enol of acetone—but at the center C-/3 of the conjugated C=C double bond. Accordingly, an addition reaction takes place whose regioselectivity resembles that of a 1,4-addition of an organometallic compound to an 0C,/3-unsaturated carbonyl compound (see Section 10.6). 1,4-additions of enols (like in this case) or enolates (as in Section 13.6) to a,/3-unsaturated carbonyl and carboxyl compounds are referred to as Michael additions. 

The Mannich reaction of an aldehyde enol (example Formula C in Figure 12.14) or a ketonic enol (example Formula C in Figure 12.15) often proceeds beyond the hydrochloride of a /l-aminocarbonyl compound or the Mannich base. The reason is that the secondary amine or its hydrochloride, which has previously been incorporated as part of the iminium ion, is relatively easy to eliminate from these two types of product. The elimination product is an a,fi-unsaturated aldehyde (example Formula E in Figure 12.14) or an a,/l-unsaturated ketone (example Formula D in Figure 12.15)—that is, an a,/l-unsaturated carbowyl compound. Figure 13.51 will show how the Mannich reaction of a carboxylated lactonic enol provides access to an a-methylene lactone, that is, an a,/l-unsaturated carboxyl compound. 

Obviously, only nonucleophilic bases can be employed for the formation of enolates from carbonyl and carboxyl compounds. A base is nonnucleophilic if it is very bulky. The only non-nucleophilic organolithium compounds that deprotonate carbonyl and carboxyl compounds are mesityllithium (2,4,6-trimethylphenyllithium) and trityllithium (triphenylmethyllithium). However, these bases do not have any significance for the generation of enolates because of the difficulties associated with their preparation and with the separation of their conjugate acid hydrocarbons. 

The research group of Muzart and Henin studied extensively the palladium-catalyzed EDP of allyl- or benzyl-carboxylated compounds. Mainly two types of substrates, prochiral enol carbonates A and racemic (3-keto esters B, were used to afford enols C as transient species [25]. In the presence of a chiral proton source, asymmetric protonation/tautomerization of enols led to enantioenriched ketones D... 

Concerning drugs, both cationic and anionic compounds are commonly used (protonated basic side chain, protonated aza heterocycles, deprotonated carboxylic acids, enolic species, and acidic sulfonamides) (Figure 21.1). 

As an alternative to prior deprotonation of the parent carbonyl compounds, enolates can also be generated in situ from allyl /(-koto carboxylates or allyl enol carbonates by decarboxylation with simultaneous production of a 7i-allylpalladium complex 1-12. A similar utilization of / -keto acids has also been described13. The following diagram illustrates the reaction course for an allyl jS-keto carboxylate. 

This compound is called ketene hydrate by Barra et al. (1992), but carboxylic acid enol by Andraos et al. (1993). 

There are two major areas of use for nonaqueous acid-base titrations. The first is the direct determination of compounds that have definite acidic or basic properties. This includes many thousands of organic compounds. For example, many amines are basic and can be titrated. There are also numerous acidic compounds, such as sulfonic acids, phosphonic acids, carboxylic acids, enols, imides, phenols, sulfur compounds, and others which can be titrated. The second largest and most important use of nonaqueous acid-base titrations is the indirect deter-... 

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