Theoretical and experimental study of the regioselectivity of Michael additions

Nucleophilic attack at an a,p-unsaturated Carbonyl moiety usually results in conjugate addition at the P-carbon atom (1,4 or Michael addition) or, occasionally, in addition at the carbonyl carbon atom (1,2 addition). Recently, however, addition at the a-carbon atom has been observed when strongly electron-withdrawing groups are positioned at the carbon atom P relative to the carbonyl group [e.g., methyl 3,3-bis(trif luoromethyl) propenoate (8) and ethyl 3-(2,4-dinitrophenyl) prop enoate (24)]. We have performed theoretical calculations tHF/6-31+G(d) and B3LYP//HF/6-31+G(d)] for the addition of cyanide anion to model alpha, beta-unsaturated carbonyl compounds to determine trends in the regioselectivity with respect to properties of the substituents. The difference between the reaction barriers for alpha- vs. beta-addition decreases as the strength of electron-withdrawing groups increases until, for sufficiently strong electron-withdrawing groups, a-addition becomes favored. The calculations are in agreement with the experimental results. We show that the regioselectivity can be predicted from partial atomic charges and properties of the frontier orbitals of the reactants. We also report new experimental evidence of a-addition to polysubstituted cinnamates and cinnamaldehydes. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004).