Enolate ions carbonyl compounds

Ab initio Hartree-Fock calculations of the stabilities of enols and carbonyl compounds (Table 5) have been performed in recent years by Hehre and Lathan (1972), Bouma et al. (1977, 1980 see also Bouma and Radom, 1978a,b) and Noack (1979). The order or magnitude of the differences in energies (AE) is the same as that estimated for acetone in the gas phase (AG = 13.9 + 2 kcal mol-1 at 25 °C) by Pollack and Hehre (1977) from an ion cyclotron resonance spectroscopy study of the proton and deuteron transfers from CD3C(OH)CD to aniline. This gave relative values for the O—H and... 

The product is an aldehyde with a hydroxy (ol) group whose trivial name is aldol. The name aldol is given to the whole class of reactions between enolates (or enols) and carbonyl compounds even if in most cases the product is not a hydroxy-aldehyde at all. Notice that the base catalyst (hydroxide ion) is regenerated in the last step, so it is truly a catalyst. 

The colors observed in this test result from the formation of a complex of the phenols with Fe(III) ion. Carbonyl compounds that have a high enol content also give a positive result in this test. The ferric chloride test works best with water-soluble phenols. A more reliable test, especially for water insoluble phenols, is the Ce(TV) test. 

The proton transfer equilibrium that interconverts a carbonyl compound and its enol can be catalyzed by bases as well as by acids Figure 18 3 illustrates the roles of hydroxide ion and water m a base catalyzed enolization As m acid catalyzed enolization protons are transferred sequentially rather than m a single step First (step 1) the base abstracts a proton from the a carbon atom to yield an anion This anion is a resonance stabilized species Its negative charge is shared by the a carbon atom and the carbonyl oxygen... 

The key intermediate m this process the conjugate base of the carbonyl compound IS referred to as an enolate ion because it is the conjugate base of an enol The term... 

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

The third major reaction of carbonyl compounds, alpha substitution, occurs at the position next to the carbonyl group—the alpha (a) position. This reaction, which takes place with all carbonyl compounds regardless of structure, results in the substitution of an a hydrogen by an electrophile through the formation of an intermediate enol or enolcite ion ... 

For reasons that we ll explore in Chapter 22, the presence of a carbonyl group renders the hydrogens on the a carbon acidic. Carbonyl compounds therefore react with strong base to yield enolate ions. 

The Sn2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C-C bonds, thereby building up larger molecules from smaller precursors. We ll study the alkylation of many kinds of carbonyl compounds in Chapter 22. 

As noted in Section 22.1, a hydrogen on the a position of a carbonyl compound is weakly acidic and can be removed by a strong base to yield an enolate ion. In comparing acetone (pK, = 19.3) with ethane (p/C, 60), for instance, the... 

Figure 22.5 Mechanism of enolate ion formation by abstraction of an a proton from a carbonyl compound. The enolate ion is stabilized by resonance, and the negative charge (red) is shared by the oxygen and the a carbon atom, as indicated by the electrostatic potential map.

Carbonyl compounds are more acidic than alkanes for the same reason that carboxylic acids are more acidic than alcohols (Section 20.2). In both cases, the anions are stabilized by resonance. Enolate ions differ from carboxylate ions, however, in that their two resonance forms are not equivalent—the form with the negative charge on oxygen is lower in energy than the form with the charge on carbon. Nevertheless, the principle behind resonance stabilization is the same in both cases. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced even more. Table 22.1 thus shows that compounds such as 1,3-dikotoncs (/3-diketoncs). 3-oxo esters (/3-keto esters), and 1,3-diesters are more acidic than water. This enhanced acidity of jS-dicarbonyl compounds is due to the stabilization of the resultant enolate ions by delocalization of the negative charge over both carbonyl groups. The enolate ion of 2,4-pentanedione, for instance,... 

Enolate ions are more useful than enols for two reasons. First, pure enols can t normally be isolated but are instead generated only as short-lived intermediates in low concentration. By contrast, stable solutions of pure enolate ions are easily prepared from most carbonyl compounds by reaction with a strong base. Second, enolate ions are more reactive than enols and undergo many reactions that enols don t. Whereas enols are neutral, enolate ions are negatively charged, making them much belter nucleophiles. As a result, enolate ions are more common than enols in both laboratory and biological chemistry. 

The a-substitution reaction of a carbonyl compound through either an enoi or enolate ion intermediate is one of the four fundamental reaction types in carbonyl-gron p chem istrv. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

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

O A carbonyl compound with an rr hydrogen atom is converted by base into its enolate ion. 

The enolate ion acts as a nucleophilic donor and adds to the electrophilic carbonyl group of a second carbonyl compound. 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

Neither benzaldehyde nor formaldehyde can form an enolate ion to add to another partner, yet both compounds have an unhindered carbonyl group. 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an ,j6-unsaturated carbonyl compound—a process known as the Michael reaction. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Michael reaction (Section 23.10) The conjugate addition reaction of an enolate ion to an unsalurated carbonyl compound. 

C-coupling is of outstanding importance in the azo coupling reaction for the synthesis of azo dyes and pigments. An aromatic or heteroaromatic diazonium ion reacts with the so-called coupling component, which can be an aromatic primary, secondary, or tertiary amine, a phenol, an enol of an open-chain, aromatic, or heteroaromatic carbonyl compound, or an activated methylene compound. These reactions at an sp2-hybridized carbon atom will be discussed in Chapter 12. In the... 

Kuwajima (75) has provided full details of the regiospecific monoalkylation of carbonyl compounds via their silyl enol ethers, using stoichiometric amounts of fluoride ion. Noyori (76) has given more information on the use of the complex fluoride source (2) (Chapter 18)... 

This area of reactivity has been the subject of excellent reviews (J5). Silyl enol ethers are not sufficiently nucleophilic to react spontaneously with carbonyl compounds they do so under the influence of either Lewis acids or fluoride ion, as detailed above. Few clear trends have emerged from the somewhat limited number of definitive studies reported so far, with ambiguities in diastereoisomeric assignments occasionally complicating the issue even further. 

This reaction illustrates the striking difference in behavior between carboxylic esters on the one hand and aldehydes and ketones on the other. When a carbanion such as an enolate ion is added to the carbonyl group of an aldehyde or ketone (16-41), the H or R is not lost, since these groups are much poorer leaving groups than OR. Instead the intermediate similar to 146 adds a proton at the oxygen to give a hydroxy compound. 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

The enolization product depends on the structure of the carbonyl substrate When //-OH is present in the carbonyl compound, (Z)-enolate is the major product due to the metal ion chelation,200 whereas (fs)-enolate is the major product in the absence of a //-OH group.22 It is worth noting that the yield is normally low for //-OH carbonyl substrates because of the tendency for //-elimination. 

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