Lipase-Catalyzed Synthesis of Substituted Phenylacetamides: Hammett Analysis and Computational Study of the Enzymatic Aminolysis

GUADALUPE GARCÍA LIÑARES; PAU ARROYO MAÑEZ; ALICIA BALDESSARI

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2014 vol. 2014 p. 6439 - 6450

1434-193X

A series of hydroxy-, mehtoxy- and nitrophenylacetamides was enzymatically synthesized. Twenty eight new products were obtained through a lipase-catalyzed two reaction steps in very good to excellent yield. In the case of nitro derivatives, a one-pot two-steps methodology allowed to obtain the desired products in high yields. The influence of various reaction parameters in the lipase-catalyzed reactions, such as enzyme source, nucleophile (alcohol or amine)/substrate ratio, enzyme/substrate ratio, solvent and temperature, was studied. Regarding the substrates, it was observed that nitro-substituted phenylacetates were more reactive in the aminolysis reaction than the phenylacetates substituted with hydroxyl group. In order to study this substituent effect, a Hammett analysis and the determination of r parameter were carried out. Moreover, a computational study was applied to the most representative systems, performing an exploration of the potential energy surface for the catalyzed and non-catalyzed aminolysis reaction for nitro- and hydroxyphenylacetates. Both analysis showed that the presence of a strongly electron-attracting group favors the activity of the enzyme, in complete agreement with the experimental results of the enzymatic catalysis.