Acid-base catalysis enol formation

Cyclodextrins with two imidazole groups on the primary hydroxyl side can enhance the enolate formation [86] of a simple bound ketone by bifunctional acid-base catalysis and accelerating the intramolecular aldol condensation of bound ketoaldehyde and dialdehyde. The aldolase mimics which catalyzed crossed aldol condensations were obtained by the assembly of (i-CD and various amino moieties as Schiff base [87]. 

Chen et al. [26] reported the use of a bifunctional thiourea catalyst 61 during the organocatalyzed thia-Michael addition of thiophenol to unsaturated imide 58c (Scheme 3.29). Michael adduct 60c was obtained in 60% ee and 97% yield by conducting the reaction in dichloromethane at -78°C. The authors speculated that while the tertiary amine of the bifunctional catalyst 61 would act as a proton shuttle according to a Brpnsted acid/base catalysis, the presence of the thiourea moiety might possibly cooperate in the stabilization of the more stable Z-enolate intermediate via hydrogen bond formation as illustrated in Scheme 3.31. 

These results establish that the base-catalyzed dehydration is slow relative to the reverse of the addition phase for the branched-chain isomer. The reason for selective formation of the straight-chain product under conditions of base catalysis is then apparent. In base, the straight-chain ketol is the only intermediate which is dehydrated. The branched-chain ketol reverts to starting material. Under acid conditions, both intermediates are dehydrated however, the branched-chain ketol is formed most rapidly, because of the preference for acid-catalyzed enolization to give the more substituted enol (see Section 7.3 of Part A). 

W-Alkylidene derivatives of glycine esters are the preferred starting compounds for the synthesis of unnatural amino acids via the deprotonation/alkylation procedure. Enolate formation is achieved with a strong base (LDA, BuLi, or phosphazene bases such as 2- tert-butylimino)-2-(ethylamino)-l,3-dimethyl-l,3,2-diazaphosphinane) or by phase-transfer catalysis (tetraalkylammonium salts with NaOH or the latter method allows... 

France S, Shah MH, Weatherwax A, Wack H, Roth JP, Lectka T (2(X)5) Bifunctioneil Lewis acid-nucleophile-based asymmetric catalysis mechanistic evidence for imine activation working in tandem with chiral enolate formation in the synthesis of p-lacttuns. J Am Chem Soc 127 1206-1215... 

These experiments employing acidic media were at best only semi-quantitative, and none comprised a systematic investigation of the catalysis. Nevertheless, they placed the transformation in a new light and broadened the opportunities for investigating its mechanism. From the dependence of the reactions on the concentrations of formate, acetate, or succinate ions, Ashmarin argued for a general add and base catalysis. The results of Petuely s experiments implied the same kind of catalytic effect, and Petuely wrote the reaction as an enolization catalyzed by acids and bases. 

The required aldol condensation, whether base- or acid-catalysed, exerts regioselectivity in the case of unsymmetrical ketones. For instance, the quinoline formation from methyl ethyl ketone and 2-benzoylaniline 66 occurs by base catalysis via the enolate giving the 2-ethyl-4-phenylquinoline 67. However, under acid catalysis via the enol, it affords 2,3-dimethyl-4-phenylquinoline 68 ... 

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. ... 

Now, formation of an enolate anion (base catalysis) or the enol itself (acid catalysis) is generally fast and reversible so that the rate determining step is that one in which a a bond is made between the two carbon atoms. 

Mechanism of enol formation under both acid-catalyzed and base-catalyzed conditions, (a) Acid catalysis involves (D) initial protonation of the carbonyl oxygen followed by ( ) removal of H from the a position, (b) Base catalysis involves (Q) initial deprotonation of the a position to give an enolate ion, followed by (0) reprotonation on oxygen. 

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 reaction can, however, be made preparative for (91) by a continuous distillation/siphoning process in a Soxhlet apparatus equilibrium is effected in hot propanone over solid Ba(OH)2 (as base catalyst), the equilibrium mixture [containing 2% (91)] is then siphoned off. This mixture is then distilled back on to the Ba(OH)2, but only propanone (b.p. 56°) will distil out, the 2% of 2-methyl-2-hydroxypentan-4-one ( diacetone alcohol , 91, b.p. 164°) being left behind. A second siphoning will add a further 2% equilibrium s worth of (91) to the first 2%, and more or less total conversion of (90) — (91) can thus ultimately be effected. These poor aldol reactions can, however, be accomplished very much more readily under acid catalysis. The acid promotes the formation of an ambient concentration of the enol form (93) of, for example, propanone (90), and this undergoes attack by the protonated form of a second molecule of carbonyl compound, a carbocation (94) ... 

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