Base catalysis of enolization

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. 

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... 

The reference intermolecular reaction is general base catalysis of the enolization of the substrate by external acetate Bell and Covington, 1975... 

The original experimental evidence for concerted acid-base catalysis of the mutarotation in benzene is now considered unsound133 134 and concerted acid-base catalysis has been difficult to prove for nonenzy-matic reactions in aqueous solution. However, measurements of kinetic isotope effects seem to support Swain and Brown s interpretation.135 Concerted acid-base catalysis by acetic acid and acetate ions may have been observed for the enolization of acetone136 and it may be employed by enzymes.1363... 

Apparently, these results implied an inverse relationship between reactivity and selectivity, with the reactivity of the carbocation measured by the inverse of the rate constant for solvolysis. This indeed was not unexpected in the context of a general perception that highly reactive reagents, especially reactive intermediates such as carbocations, carbanions, or carbenes are unselective in their reactions.257 259 Such a relationship is consistent with a natural inference from the Hammond postulate258 and Bell-Evans-Polanyi relationship,260 and is illustrated experimentally by the dependence of the Bronsted exponent for base catalysis of the enolization of ketones upon the reactivity of the ketone,261,262 and other examples21,263 including Richard s careful study of the hydration of a-methoxystyrenes.229... 

The curves for log(kK/s ) and log(kK/s ) of acetophenone are parallel in the range pAT << PH << pAT and the vertical distance between them then equals pAtE = log(kK/s 1) — log /s-1). Most ketones are very weak bases, pAt < 0, so that the parameter does not affect the shape of the pH-rate profiles in the range pH > 1. Base catalysis of ketonization saturates at pH = pAr , while the rate of enolization continues to rise, so that the curves for kE and kK eventually cross at higher pH. At still higher pH, the rate constant kE exceeds that of kK = k o and kobs follows kK. The crossing point, for which kE = kK, lies at pH = pAT = 18.3 for acetophenone (Fig. 3), which is outside the accessible pH range when ionic strength I is limited to 0.1 m, but pA is readily calculated from Equation (2). 

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... 

Base catalysis of keto-enol equilibration involves an enolate anion intermediate. 

Base or (Lewis) acid catalysis leads to different products of Friedlander synthesis with unsymmetrical a-CH2 ketones, as exempHfied for the cydocondensation of (2-amino)benzophenone and methyl ethyl ketone Base catalysis (via enolate) gives rise to 2-ethyl-4-phenylquinoHne (80) as main product, while (Lewis) add catalysis (via enol)... 

Nature s aldolases use combinations of acids and bases in their active sites to accomplish direct asymmetric aldolization of unmodified carbonyl compounds. Aldolases are distinguished by their enolization mode - Class I aldolases use the Lewis base catalysis of a primary amino group and Class II aldolases use the Lewis acid catalysis of a Zinc(II) cofactor. To accomplish enolization under essentially neutral, aqueous conditions, these enzymes decrease the pKa of the carbonyl donor (typically a ketone) by converting it into a cationic species, either an iminium ion (5) or an oxonium ion (8). A relatively weak Bronsted base co-catalyst then generates the nucleophilic species, an enamine- (6) or a zinc enolate (9), via deprotonation (Scheme 4.2). 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

Solutions of unstable enols of simple ketones and aldehydes can also be generated in water by addition of a solution of the enolate to water. The initial protonation takes place on oxygen, generating the enol, which is then ketonized at a rate that depends on the solution pH. The ketonization exhibits both acid and base catalysis. Acid catalysis involves C-protonation with concerted 0-deprotonation. 

It is not the aldehyde or ketone itself that is halogenated, but the corresponding enol or enolate ion. The purpose of the catalyst is to provide a small amount of enol or enolate. The reaction is often done without addition of acid or base, but traces of acid or base are always present, and these are enough to catalyze formation of the enol or enolate. With acid catalysis the mechanism is... 

The ot-ketol rearrangement can also be brought about by base catalysis, but only if the alcohol is tertiary, since if or = hydrogen, enolization of the substrate is more favored than rearrangement. 

Lewis-Base Catalysis via Intermediate Formation of a Chiral Zwitterionic Enolate... 

Enantioselective Catalysis of the Aldol Addition Reaction. There are also several catalysts that can effect enantioselective aldol addition. The reactions generally involve enolate equivalents, such as silyl enol ethers, that are unreactive toward the carbonyl component alone, but can react when activated by a Lewis acid. The tryptophan-based oxazaborolidinone 15 has proven to be a useful catalyst.148... 

The intermediate N-acylpyridinium salt is highly stabilized by the electron donating ability of the dimethylamino group. The increased stability of the N-acylpyridinium ion has been postulated to lead to increased separation of the ion pair resulting in an easier attack by the nucleophile with general base catalysis provided by the loosely bound carboxylate anion. Dialkylamino-pyridines have been shown to be excellent catalysts for acylation (of amines, alcohols, phenols, enolates), tritylation, silylation, lactonization, phosphonylation, and carbomylation and as transfer agents of cyano, arylsulfonyl, and arylsulfinyl groups (lj-3 ). 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

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... 

There is room for further analysis in many traditional areas, as pointed out above during the discussion of enolization. Also, it is noted that the employment of transition state pKf values is very close to the use of the proton activating factors and deprotonating factors, introduced by Stewart (Stewart and Srinivasan, 1978 Stewart, 1985). It is to be hoped that the two approaches can be consolidated in a common view of acid-base catalysis. 

One class of reaction, conventionally designated as intramolecular general base catalysis, which is actually unimolecular is enolization catalysed by a neighbouring basic centre [22]. It might be thought that this reaction has as... 

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