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Theoretical and Experimental Study of the Regioselectivity of Michael Additions
Author(s) -
Chatfield David C.,
Augsten Alberto,
D'Cunha Cassian,
Lewandowska Elzbieta,
Wnuk Stanislaw F.
Publication year - 2004
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200300523
Subject(s) - chemistry , regioselectivity , michael reaction , nucleophile , polar effect , moiety , addition reaction , carbon atom , nucleophilic addition , cinnamates , trifluoromethyl , medicinal chemistry , computational chemistry , organic chemistry , catalysis , ring (chemistry) , alkyl
Nucleophilic attack at an α,β‐unsaturated carbonyl moiety usually results in conjugate addition at the β‐carbon atom (1,4 or Michael addition) or, occasionally, in addition at the carbonyl carbon atom (1,2 addition). Recently, however, addition at the α‐carbon atom has been observed when strongly electron‐withdrawing groups are positioned at the carbon atom β relative to the carbonyl group [e.g., methyl 3,3‐bis(trifluoromethyl)propenoate ( 8 ) and ethyl 3‐(2,4‐dinitrophenyl)propenoate ( 24 )]. We have performed theoretical calculations [HF/6−31+G(d) and B3LYP//HF/6−31+G(d)] for the addition of cyanide anion to model α,β‐unsaturated carbonyl compounds to determine trends in the regioselectivity with respect to properties of the substituents. The difference between the reaction barriers for α‐ vs. β‐addition decreases as the strength of electron‐withdrawing groups increases until, for sufficiently strong electron‐withdrawing groups, α‐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 α‐addition to polysubstituted cinnamates and cinnamaldehydes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)