Conformational Effects on the Aldol Reaction

The importance of the aldol reaction in synthetic organic chemistry cannot be overstated. In this regard, controlling the stereochemistry of the reaction has received extensive investigation. Entire chapters have been written about just this one facet of synthetic organic 

When the two carbonyl-containing species of the aldol reaction are the same, then a simple reflux in basic ethanol will lead to the reaction (Eq. 11.13). However, when two different carbonyls are involved, special precautions must be taken to avoid an intractable mixture of products. Enolate formation is achieved first, and the reaction conditions should promote quantitative and irreversible enolate formation. Typically, an aldehyde is required as the electrophilic carbonyl component, so that the addition reaction is fast. In this way, complications involving proton transfer from the ot-carbon of the carbonyl to the enolate, making a new enolate, are avoided. 

For example, consider the reaction of the enolate of cyclohexanone with 1-butanal (Eq. 11.15). Here, the nucleophile is first created by treatment with a strong base, followed by addition to the electrophile. Under proper conditions, no enolate from 1-butanal is formed, and a single product is isolated (ignoring stereoisomers). This is referred to as a mixed aldol reaction. 

Analysis of conformational effects on aldol reactions. A. The equilibria and products from Z-enolates. B. The equilibria and products from -enolates. 

While we have just described the simplest of aldol reactions, the analysis is quite representative. Chelation control and application of the rules of conformational analysis to reaction transition states are common aspects of the analysis of more advanced aldol systems. 

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