Knoevenagel reaction steric effects

Virtually any aldehyde or ketone and any CH-acidic methylene compound can be employed in the Knoevenagel reaction however the reactivity may be limited due to steric effects. Some reactions may lead to unexpected products from side-reactions or from consecutive reactions of the initially formed Knoevenagel product. 

There is almost no restriction in the choice of an appropriate electrophile in the Knoevenagel reaction. Aldehydes, ketones, thioketones, imines, enamines, acetals and orthoesters have been used. With less reactive methylene groups, however, drastic reaction conditions may be necessary. Steric effects have a significant influence on the rate and unexpected compounds are often obtained as a result of secondary reactions. Reaction of 1,3-dicarbonyl compounds with carbon disulfide followed by dialkylation with an alkyl halide give diacylketene-S,5-acetals (159). However, even with highly acidic dicarbonyl com-... 

The Knoevenagel reaction is, moreover, sensitive to both electronic and steric effects, making aryl carbonyls less reactive than alkyl-substituted analogs, and ketones much less active than aldehydes. Macquarrie et al. studied the condensation of a range of carbonyl components with ethyl cyanoacetate, using AMPS, and found that the order of activity of the carbonyl component was as expected... 

A closely related methodology was applied by Zhao et al. to the enantio-selective synthesis of tetrasubstituted thiochromanes on the basis of a domino thia-Michael-Knoevenagel reaction between 2-mercaptobenzaldehydes and benzylidenemalonates with the same quinine thiourea catalyst. Steric and electron effects were found to affect profoundly the stereoselectivities of the reaction. Thus, it was shown that the diastereoselectivity of the reaction... 

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