Catalysis of Enolizations

Enolization can be either acid- or base-catalyzed, and general catalysis mechanisms have been observed. With general-base catalysis, deprotonation of the a-carbon in the first step is rate-determining. Protonation of the enolate oxygen gives the enol (Eq. 11.1). Both reactions in the second equilibrium of Eq. 11.1 are faster than the initial deprotonation of the a-carbon of the keto form. 

Evidence that deprotonation is rate-determining in the general-acid-catalyzed enolization of a carbonyl comes from studying the reverse reaction. The rate of conversion of the enol of cyclohexanone to cyclohexanone has been measured (Eq. 11.3). It occurs at the same rate as the hydrolysis of 1-methoxycyclohexene (Eq. 11.4), where protonation of the double bond of the enol ether is known to be rate-determining. The coincidence is interpreted to mean that protonation is rate-determining in both reactions of Eqs. 11.3 and 11.4. Hence, by microscopic reversibility, if protonation of the double bond of the enol is rate-determining in the formation of the ketone, it follows that deprotonation of the a-carbon is rate-determining in the formation of the enol (Eq. 11.2). 

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The primary literature now contains a very large body of kinetic data for the catalysis of enolization and ketonization, not only of ketones and aldehydes but also of )3-diketones, )3-keto esters, and dienones, much of which could be treated by the Kurz approach. Also, data exist for third-order enolization, due to combined general acid and base catalysis, that could also be analysed. Such treatment is beyond the scope the present review. However, one study of metal ion catalysis of enolization is discussed later in this section. 

F. l Catalysis of ester hydrolysis 264, F.2 Catalysis of enolization 265 G Intramolecular general base catalysis by nitrogen 266... 

Tee s group has reported on the catalysis of enolization of indan-2-one (200) by a-CD, [1-CD, y-CD, hydroxyethyl-jS-CD, and hydroxypropy I -/i-C D, all of which accelerate the reaction by up to 22-fold, but dimethyl-jS-CD slows it by about half.170 These workers have also looked at the effect of alcohols on the basic cleavage of m-nitrophenyl hexanoate by /1-CD.171 Finally, they have been examining the reaction of a-amino acid anions with p-nitrophenyl acetate and hexanoate in the presence of [1-CD.172... 

Results of a study of electrostatic acceleration of enolization in cationic ketones have implications for enzymatic catalysis of enolization.136 Rate constants determined for water-, acetate- and hydroxide ion-catalysed enolizations of cationic ketones (79) (pK 11.13) and (80) (pK 11.90) have been compared with those for (81). It has been estimated that the inductive effects of the charged lings lower the p/y,s of (81) and (79) by 4.2 and 1.2 log units, respectively, whereas for (79) the electrostatic effect lowers the pAa by 6.3 log units, and enhances oh by 330-fold relative to a typical methyl ketone. The rate of enolization of (81) is enhanced 2.3 x 104-fold by the through-space electrostatic effect. 

Fig. 9 Variation of the Bronsted parameter a for general acid catalysis of enol ketonization with the free energy change AG° for carbon protonation of enols (o) and enolates ( ). The data are taken from Table 2.

Fig. 2 Unit-slope relation between the logarithms of rate constants for hydronium-catalysis of enol ketonisation (fcket0) and enol ethyl ether hydrolysis (fchydro) n the series of cycloalkanone (C H2 20) derivatives (Dubois et al., 1981)...

Atom Variations E2 Heteroatom Variants, Dehalogenation, Fragmentation Vinylogous Variations Sn2 and E2. 1,4 additions Extent of Proton Transfer Variations General Acid and General Base Catalysis of Additions and Eliminations, Summary by Media, Push-Pull Catalysis of Enolization... 

Lead tetraacetate reacts with ketones to form a-acetoxyketones. Reported yields are seldom high, however. The reaction has been successfully applied to keto steroids. Boron trifluoride can be used to catalyze these oxidations. It is presumed to function by catalysis of enolization, and it is assumed that the enol is the reactive species. ... 

Acid catalysis of enol formation and base catalysis of enolate formation are also key steps in the aldol reaction. " The base-catalyzed reaction is shown in Figure 7.11, and the acid-catalyzed reaction is illustrated in Figure 7.12. The analogous reaction involving ketones is usually not synthetically useful because addition of an enolate ion to a ketone is less favorable than is addition to an aldehyde. ... 

Another promising system involves the concerted acid/base catalysis of enolization of ketones. Stereoelectronic considerations [25] indicate that an optimal catalyst for this reaction requires that acid and base components converge from perpendicular directions on the ketone (Scheme 12). The structure 27 (a glycine derivative of Kemp s triacid) exhibits considerable activity in the enolization of phenylacetone. It should be possible to engineer additional points of contact between ketone (substrate) and diacid (catalyst) to enhance the enolization process, and we are working toward this goal. 

Mechanistic studies show how the hydrolysis of RNA is catalyzed by imidazole buffer, and this information was used in the design of an effective catalyst for a related process. The geometric preference of this catalyst is evidenced in the greater effectiveness of one isomer, but another isomer is preferred for bifunctional catalysis of enolization and of an internal aldol condensation. 

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