Theoretical study of reaction mechanism and regioselectivity of spiro-isoxazoline derivatives synthesized by intermolecular 1,3-dipolar cycloaddition

The reaction mechanism and regioselectivity of spiro-isoxazoline derivatives synthesized by an intermolecular 1,3-dipolar cycloaddition reaction between 2,6-dichlorobenzonitrile oxide and 3-(4-chlorobenzylidene)dihydrofuran-2-one were studied using density functional theory and ab initio theory. Two possible reaction channels, which are related to the formation of isoxazoline-5-spiro-cyclic (Channel 1) and isoxazoline-4-spiro-cyclic (Channel 2) are investigated using natural bond orbital analysis, geometrical parameters analysis, energy analysis and frontier molecular orbital (FMO) analysis. The energy analysis shows that both the activation energy and reaction energy for Channel 2 are higher than those for Channel 1. The larger activation energy prevents the formation of isoxazoline-4-spiro-cyclic. Therefore, isoxazoline-5-spiro-cyclic is formed as the energetically favored product. The FMO analysis shows that the regioselectivity of this reaction is controlled by the LUMOdipole-HOMOdipolamphile interaction, and the reaction proceeds via Channel I which agrees with the experimental results. The natural bond order analysis shows the reaction follows a concerted mechanism with two bonds formed at about the same time. (C) 2004 Elsevier B.V. All rights reserved.