Multiple-Factor-Regulated Enantioselectivity by Halogen Bond Catalysis

Halogen bond (XB) catalysis provides a sustainable, metal-free strategy for organic synthesis, yet precise control over high enantioselectivity remains a key challenge. Elucidating the microscopic mechanism of XB catalyst selectivity is one of the most significant approaches for the development of superior XB catalysts. Herein, we investigate three iodine(III)-based and four bidentate iodine(I)-based XB donors in the Pictet-Spengler reaction of benzaldehyde and N-benzyltryptamine (for chiral tetrahydro-β-carbolines, THβCs) via density functional theory (DFT) calculations, coupled with complementary static and thermodynamic analysis. The catalytic cycle consists of six key steps, with XB catalysts activating the carbonyl group of benzaldehyde through I···O XB. The bidentate iodine(III)-based catalyst, which integrates a bidentate structure with an iodine(III) center, demonstrated superior activity and selectivity among all seven evaluated catalysts. Reaction energy barriers exhibit a linear correlation not only with the electron density at the bond critical point (BCP) of the I···O interaction (as determined by the quantum theory of atoms in molecules, QTAIM) but also with the integral of carbonyl oxygen charge rearrangement. Electrostatic and polarization interactions dominate the attractive forces between catalysts and substrates. Thermodynamic analysis reveals excellent enantioselectivity ((S)-P: (R)-P > 90:10) among the tested catalysts, the iodine(III)-pyrazolium-based (cat-1) and bidentate iodine(III)-based (cat-3) XB donors exhibit the highest enantiomeric excess ((S)-P: (R)-P ≥ 99:1), attributed to the configuration transformation from (R)-P to (S)-P. Notably, thermodynamic results demonstrate that the steric hindrance arising from the energy barrier difference among various reaction pathways is not the sole determinant of enantioselectivity; the interconversion between different enantiomers also plays a crucial role. This work clarifies the XB catalytic mechanism of the Pictet-Spengler reaction, compares the catalytic performance of iodine(III)-based and bidentate iodine(I)-based XB catalysts, reveals the multifactor-controlled mechanism in regulating the enantioselectivity, and provides theoretical guidance for the rational design of efficient enantioselective XB catalysts.