Aldol condensation steric factors

The exact position of the aldol equilibrium depends both on reaction conditions and on substrate structure. The equilibrium generally favors condensation product in the case of aldehydes with no a substituent (RCH2CHO) but favors reactant for disubstituted aldehydes (R2CHCHO) and for most ketones. Steric Factors are probably responsible for these trends, since increased substitution near the reaction site increases steric congestion in the aldol product. 

The reaction step of heterocyclization of iminocarbonyl compounds 136 is probably the rate-limiting stage, as for monocyclic pyrylium salts [82AHC(Suppl)]. Its rate is determined by the electrophilicity of the carbonyl group and by steric factors. In the case of a bulky 3-aryl group, especially with donor substituents, the rate of heterocyclization should be retarded, and because of this influence, the behavior of 136 becomes dependent on the nature of R3. Thus, if R3 = Me or Et, the possibility of intramolecular aldol-type condensation is real, and a-naphthylamines 140 are formed (82KGS552). 

It is important to put the thermodynamic aldol condensation into perspective. The actual product as well as the yield depends on the solvent, the base used, and the nature of the carbonyl substrate. When both a kinetic and a thermodynamic enolate are present, the equilibrium may favor the thermodynamic enolate, but steric hindrance makes its reaction much slower. In such a case, the kinetic enolate product may be the isolated product. When 2-pentanone (32) is refluxed with NaOMe in methanol and then treated with 20% sulfuric acid, for example, conjugated ketone 42 is the only isolated product, but in only 8% yield. This clearly makes the reaction confusing to understand. It is presented only to show that this reaction is an equilibrium-driven process and that the equilibrium may be shifted between kinetic and thermodynamic enolates by several factors. For the purposes of doing homework, assume that thermodynamic conditions lead to the thermodynamic aldol as the major product and that kinetic control conditions lead to the kinetic aldol as the major product. 

To elucidate the steric factors involved in visual pigment formation (Ebrey et aL, 1975 Nakanishi, 1977 Shichida 7 a/., 1981), derivatives of retinaldehyde (2) that contain additional methyl substituents in their side chains have been synthesized (Tanis etal., 1978). A modification of Wittig s directed aldol condensation was employed for chain-lengthening. p-Ionone (125) reacted with lithiated propylidenecyclohexylamine (518) to give the isomeric aldehydes (519) and (520), which were purified by HPLC. Condensation of the trans aldehyde (519)... 

In addition to steric interactions, other structural features may influence the stereoselectivity of aldol condensations. One such factor is chelation by a donor substituent. Several )8-alkoxyaldehydes show a preference for syn aldol products on reaction with Z-enolates. A chelated transition state can account for the observed stereochemistry. The chelated aldehyde is most easily approached from the face opposite the methyl and R substituents. 

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