Enolization of Aldehydes and Ketones

Transformation of a carbonyl compound to an enol at a useful rate normally requires either a basic catalyst or an acidic catalyst and, of course, at least one hydrogen on the a carbon. The features of each type of catalysis follow. 

With a basic catalyst such as hydroxide ion, the first step in enolization is removal of a proton from the a position to give the enolate anion 1  

Normally, C-H bonds are highly resistant to attack by basic reagents, but removal of a proton alpha to a carbonyl group results in the formation of a considerably stabilized anion with a substantial proportion of the negative charge on oxygen, as represented by the valence-bond structure 1a. Carbonyl compounds such as 2-propanone therefore are weak acids, only slightly weaker than alcohols (compare the pKa values for some representative compounds in Table 17-1).1 

1The important difference between 2-propanone and ethanol as acids is that the rate of establishment of equilibrium with 2-propanone or similar compounds where ionization involves breaking a C-H bond is very much slower than the corresponding reaction with O-H bonds. 

Two carbonyl groups greatly increase the acidity. For example, 2,4-pentanedione (acetylacetone, 2) has a pATa s 9, which is comparable to the O—H acidity of phenols (see Table 17-1). The reason is that the enolate anion 3 has the charge largely shared by the two oxygen atoms (cf. 3b and 3c). As a result, the enolate anion 3 is stabilized more with respect to the 

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You have had earlier experience with enols m their role as intermediates m the hydration of alkynes (Section 9 12) The mechanism of enolization of aldehydes and ketones is precisely the reverse of the mechanism by which an enol is converted to a carbonyl compound... 

The stereochemical outcome of the addition of lithium enolates of aldehydes and ketones to nitroalkenes is dependent upon the geometry of the nitroalkene and the enolate anion. The synjanti selectivity in the reaction of the lithium enolates of propanal, eyelopentanone and cyclohexanone with ( )- and (Z)-l-nitropropene has been reported1. 

The enolization of aldehydes and ketones [35] —> [36] is subject to both acid and base catalysis (Bell, 1973 Toullec, 1982 Albery, 1982). Although the kinetics of the reaction were first studied 90 years ago (Lapworth, 1904) and... 

Trimethylsilyl enolates of aldehydes and ketones are now established as highly useful synthetic intermediates.2 In particular, their Lewis acid-catalyzed reactions - e.g., alkylation 1 and mild, regiospecific aldol... 

Other reactions of carbohydrates include those of alcohols, carboxylic acids, and their derivatives. Alkylation of carbohydrate hydroxyl groups leads to ethers. Acylation of their hydroxyl groups produces esters. Alkylation and acylation reactions are sometimes used to protect carbohydrate hydroxyl groups from reaction while a transformation occurs elsewhere. Hydrolysis reactions are involved in converting ester and lactone derivatives of carbohydrates back to their polyhydroxy form. Enolization of aldehydes and ketones leads to epimerization and interconversion of aldoses and ketoses. Addition reactions of aldehydes and ketones are useful, too, such as the addition of ammonia derivatives in osazone formation, and of cyanide in the Kiliani-Fischer synthesis. Hydrolysis of nitriles from the Kiliani-Fischer synthesis leads to carboxylic acids. 

Finally, acid-catalyzed enolization of aldehydes and ketones in the presence of selenium dioxide (SeO ) also results in oxidation a- to those carbonyl functionalities via the corresponding enol. As shown in Scheme 8.14, the reaction of the enol with Se02 followed by the loss of selenium(II) oxide (which subsequently... 

The position of equilibrium is less favorable for ketones, but hydroxide and alkoxides are sufficiently basic to catalyze the enolization of aldehydes and ketones by way of the enolate as an intermediate. 

The reactions of the enolates of aldehydes and ketones with copper (II) salts have been known for many years to yield a-acylcarbon-centered radicals which couple to form 1,4-dicarbonyl compounds in nearly quantitative yields (i-J).We have found that the radicals that are intermediates in these reactions are useful for initiating polymerization reactions and have shown that these reactions are very valuable for the synthesis of polymers with useful end-group functionality, block copolymers and graft copolymers 4-8). 

In the following sections, we focus on condensation reactions at the a-carbon atom of esters. Reactions of these derivatives form carbon—carbon bonds and are useful in synthesis. Alkylation reactions using alkyl halides and reactions at carbonyl carbon atoms both occur with ester enolates. However, the reactions of enolates of acid derivatives differ somewhat from the reactions of enolates of aldehydes and ketones. For one thing, the a-hydrogen atoms of esters (pA 25) are less acidic than those of aldehydes and ketones (pif 20). Two resonance forms are written for aldehydes and ketones. The dipolar resonance form of a ketone has a positive charge on an electron-deficient carbonyl carbon atom. The contribution of this resonance form (2) to the resonance hybrid increases the acidity of the a-hydrogen atom as the result of inductive electron withdrawal. 

In Section 22.2, we considered the types of bases required to generate an enolate of aldehydes and ketones. We recall that relatively weak bases, such as alkoxide ions, give only low concentrations of the enolates of ketones. Because esters are weaker acids than ketones, even lower concentrations of ester enolates form in reactions with alkoxide ions. The alkoxide base must be the same as the alkoxy group contained in the ester to avoid exchange of alkoxy groups. 

The enolates of aldehydes and ketones undergo deuterium exchange, bromination, and alkylation reactions (Sections 22.4—22.6). Carboxylic acid derivatives react similarly. However, the added possibility of a competing nucleophilic acyl substitution reaction limits some of the substitution reactions at the a-carbon atom of acid derivatives. For example, acyl halides react with most bases in substitution reactions at the carbonyl carbon atom rather than by abstraction of the a-hydrogen atom. On the other hand, the pA of the a-hydrogen atoms of amides is very large, and these derivatives would require a very strong base for formation of enolates for synthetic reactions. Esters are the most convenient acyl derivatives for enolate formation and subsequent substitution at the a-carbon atom. The substituted ester can subsequently be converted into other acyl derivatives. 

The zinc enolate can potentially react with an electrophilic carbonyl carbon atom or at the oxygen atom of the enolate. However, we recall that similar reactions of enolates of aldehydes and ketones occur at carbon, thus retaining the very stable carbonyl group. The same considerations are important for the reactions of ester enolates, which also react at the carbonyl carbon. 

In the preceding chapter you learned that nucleophilic addition to the carbonyl group IS one of the fundamental reaction types of organic chemistry In addition to its own reactivity a carbonyl group can affect the chemical properties of aldehydes and ketones m other ways Aldehydes and ketones having at least one hydrogen on a carbon next to the carbonyl are m equilibrium with their enol isomers... 

As m the acid catalyzed halogenation of aldehydes and ketones the reaction rate is mde pendent of the concentration of the halogen chlorination brommation and lodmation all occur at the same rate Formation of the enolate is rate determining and once formed the enolate ion reacts rapidly with the halogen... 

A number of novel reactions involving the a carbon atom of aldehydes and ketones involve enol and enolate anion intermediates... 

Reactions of Aldehydes and Ketones That Involve Enol or Enolate Ion Intermediates... 

Because enolate anions ffle sources of nucleophilic car bon, one potential use in organic synthesis is their- reaction with alkyl halides to give a-alkyl derivatives of aldehydes and ketones ... 

OL Alkylation of aldehydes and ketones (Section 18.15) Alkylation of simple aldehydes and ketones via their enolates is difficult. p-Diketones can be converted quantitatively to their enolate anions, which react efficiently with primary alkyl halides. 

Besides the aldol reaction in the true sense, there are several other analogous reactions, where some enolate species adds to a carbonyl compound. Such reactions are often called aldol-type reactions the term aldol reaction is reserved for the reaction of aldehydes and ketones. 

Enolates derived from various imino compounds have been sulfinylated in reactions analogous to those shown by equations (14) and (15). Some representative examples are shown in equations 16-18. Here again, these compounds have been utilized in asymmetric syntheses. Addition of sulfinate ester 19 to a THF suspension of a-lithio-N,N-dimethylhydrazones, derived from readily available hydrazones of aldehydes and ketones, leads to a-sulfinylhydrazones in good yield, e.g. 53 and 54 (equations 16 and 17)85,86. Compounds 53 and 54 were obtained in a 95/5 and 75/25 E/Z ratio, respectively. The epimer ratio of compound 53 was 55/45. Five other examples were reported with various E/Z and epimeric ratios. 

The a-hydrogens of carboxylic acid derivatives show enhanced acidity, as do those of aldehydes and ketones, and for the same reasons, that the carbonyl group stabilizes the conjugate base. Thus, we can generate enolate anions from carboxylic acid derivatives and use these as nucleophiles in much the same way as we have already seen with enolate anions from aldehydes and ketones. 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

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