Stabilized carbanions aldol condensation

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

Base-catalyzed transformations can be carried out elsewhere on a complex molecule in the presence of such protected -dicarbonyl magnesium chelate. For example, the chelated magnesium enolate of a /3-ketoester such as 71 prevents the carbonyl keto group becoming an acceptor in aldol condensations. However, in the presence of excess of magnesium methanolate, exchange of the acetyl methyl protons can occur via a carbanion 72 stabilized by delocalization into the adjacent chelate system (equation 99). 

MECHANISM FIGURE 14-5 The class I aldolase reaction. The reaction shown here is the reverse of an aldol condensation. Note that cleavage between C-3 and C-4 depends on the presence of the carbonyl group at C-2. and (2)The carbonyl reacts with an active-site Lys residue to form an imine, which stabilizes the carbanion generated by the bond cleavage—an imine delocalizes electrons even better than... 

An example of an a-ketol formation that does not involve decarboxylation is provided by the reaction catalyzed by transketolase, an enzyme that plays an essential role in the pentose phosphate pathway and in photosynthesis (equation 21) (B-77MI11001). The mechanism of the reaction of equation (21) is similar to that of acetolactate synthesis (equation 20). The addition of (39) to the carbonyl group of (44) is followed by aldol cleavage to give a TPP-stabilized carbanion (analogous to (41)). The condensation of this carbanionic intermediate with the second substrate, followed by the elimination of (39), accounts for the observed products (B-7IMIHOO1). 

Another example is provided by the equilibrium in the aldol condensation. Examination of the mechanism for this reaction (see Figure 20.3) shows that an enolate anion leaves in the reverse of the second step of this reaction. Again, it is the stabilization of the carbanion, this time by resonance, that enables the enolate anion to leave. 

Reaction of stabilized carbanions with carbonyl compounds Aldol condensation... 

In Fig. 2 we have represented both the r Acetone values and the total site density (nj) as a function of catalyst composition. Qualitatively, the variation of r Acetone with increasing A1 content is similar to that followed by nj thereby suggesting that acetone conversion depends on both acid and base sites. Pure MgO was the most active catalyst whereas AI2O3 showed the lowest activity. This is because Al-0 pairs are much less active than Mg-0 pairs for promoting the proton abstraction and carbanion stabilization steps involved in aldol condensation reactions. We have showed [1] that the acetone aldolization rate is controlled on basic catalysts by the number of metal cation-oxygen anion surface pairs. Mg-rich Mg AlOx oxides are less active than MgO because they exhibit a lower base site density and also poor acidic properties. In contrast, Al-rich Mg AlOx oxides are more active than AI2O3 due to a proper combination of acid and base sites. 

The resonant anion can act as a typical carbanion and add to C=0 or C=N bonds, just as a Gtignard reagent does. In a true aldol condensation, the anion after formation proceeds to interact with another molecule of the starting aldehyde or ketone, giving a product that is a beta-hydroxy aldehyde or ketone known as an aldol (Scheme 4.29). Frequently, water is eliminated from this compound to produce an a, P-unsaturated carbonyl compound this process is made easy by the resonance stabilization of such conjugated systems. 

As illustrated in Scheme 4, the gas-phase base-catalyzed aldol condensation mechanism proceeds through a bifunctional pathway because of the necessary presence of both the surface oxygen anions and Lewis acid sites. However, the role of the latter is limited to the initial activation of the reactant molecules and to stabilization of the carbanionic intermediates. A discussion on the bifunctional nature of aldol condensation reactions can be formd in Refs. (8) and (14). 

In the formation of the first synthetic intermediate in Sequence D, the very effective Verley-Doebner modification of the fundamental Knoevenagel condensation is used. This modification uses malonic acid in place of the conventional ester to promote enoUzation. In addition, the heterocyclic amine, pyridine, functions as both the base catalyst and the solvent. A cocatalyst, P-alanine (an amino acid), is also introduced. Mechanistically, the reaction closely resembles the aldol condensation in that in both cases a carbanion is generated by abstraction, by base, of a proton alpha to a carbonyl group. The resulting carbanion is stabilized as an enolate anion (see below). 

A similar series of reactions is involved in the aldol condensation, where a stabilized carbanion adds to a carbonyl group e.g.,... 

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