How the mechanism of a [3 + 2] cycloaddition reaction involving a stabilized N-lithiated azomethine ylide toward a π-deficient alkene is changed to stepwise by solvent polarity? What is the origin of its regio- and endo stereospecificity? A DFT study using NBO, QTAIM, and NCI analyses

Abstract

A theoretical study at the MPWB1K/6-31G(d) level was performed on the [3 + 2] cycloaddition (32CA) reaction of a stabilized N-lithiated azomethine ylide (AZY 1) toward a π-deficient methyl acrylate (MA 11) in tetrahydrofuran (THF) to elucidate the regio- and stereoselectivity as well as the mechanistic aspects involved in this reaction. The energetics results, in excellent agreement with the experimental findings, indicate that between the two competitive C3–C4 and C3–C5 regioisomeric channels, the former is both kinetically and thermodynamically preferred over the latter, in which the electrophilic attack of the C4 carbon atom of MA 11 on the C3 carbon atom of AZY 1 through an endo approach mode passes the endo transition state TS1n, whose Gibbs free energy is 9.8 kcal mol⁻¹ higher than those of the separate reagents. The analysis of the intrinsic reaction coordinate (IRC) curves of TS1n in the gas phase and in THF demonstrates that unlike the gas phase, the noticeable charge separation caused by the electron density delocalization from the carbonyl oxygen atom of the MA 11 moiety toward the Li cation of the AZY 1 moiety is sufficiently stabilized by the solvent polarity, leading to the formation of the zwitterionic intermediate IN1n according to a stepwise mechanism. Upon the formation of IN1n, during which the first C3–C4 single bond forms, the attractive electrostatic force between the oppositely charged C1 (+0.08e) and C5 (−0.51e) carbon atoms promotes the ring closure step via TS11n with a non-appreciable barrier of 1.3 kcal mol⁻¹, leading to the formation of a second C1–C5 single bond at the corresponding lithiated cycloadduct. The calculated electrophilic and nucleophilic Parr functions at the reactive sites of the reagents together with the presence of large steric hindrances along the unfavourable C3–C5 regioisomeric channel enables us to explain the C3–C4 regiospecificity observed experimentally. In addition, the origin of the endo-stereospecificity experimentally displayed by the 32CA reaction under consideration can be nicely portrayed using non-covalent interactions (NCIs) analysis at the exo TS1x and endo TS1n transition states involved in the preferred C3–C4 regioisomeric channel.