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The Role of Noninnocent Solvent Molecules in Organocatalyzed Asymmetric Michael Addition Reactions
Author(s) -
Patil Mahendra P.,
Sunoj Raghavan B.
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200800877
Subject(s) - michael reaction , solvent , organocatalysis , chemistry , organic chemistry , enantioselective synthesis , catalysis
A proline‐catalyzed asymmetric Michael addition between ketones and trans ‐β‐nitrostyrene was studied by using the density‐functional theory with mPW1PW91 and B3LYP functionals. Improved insight into the enantio‐ and diastereoselective formation of γ‐nitroketones/‐aldehydes is obtained through transition‐state analysis. Consideration of the activation parameters obtained from gas‐phase calculations and continuum solvation models failed to reproduce the reported experimental stereoselectivities for the reaction between cyclohexanone and 3‐pentanone with trans ‐β‐nitrostyrene. The correct diastereo‐ and enantioselectivites were obtained only upon explicit inclusion of solvent molecules in the diastereomeric transition states that pertain to the CC bond formation. Among the several transition‐state models that were examined, the one that exhibits cooperative hydrogen‐bonding interactions with two molecules of methanol could explain the correct stereochemical outcome of the Michael reaction. The change in differential stabilization that arises as a result of electrostatic and hydrogen‐bonding interactions in the key transition states is identified as the contributing factor toward obtaining the correct diastereomer. This study establishes the importance of including explicit solvent molecules in situations in which the gas‐phase and continuum models are inadequate in obtaining meaningful insight regarding experimental stereoselectivities.