Halogen Bonds Concerted Catalyzed Bromo-Carbocyclization: Computational Mechanistic Insights

Halogen bond (XB)-driven catalysis, as an innovative catalytic strategy in the field of supramolecular catalysis, has demonstrated promising advantages, including environmentally benign and sustainable features in organocatalysis. Among these XB-catalyzed reactions, bromo-carbocyclization has attracted considerable attention due to its ability to simultaneously maintain high selectivity (<i>trans</i>-product:<i>cis</i>-product > 99:1) and relatively high yield in the preparation of chromane-based drug molecular framework. Particularly, the byproduct in XB-catalyzed bromo-carbocyclization could further interact with the substrate by forming a more complicated weak interaction network, which could promote the XB-catalyzed reactions by the concerted catalysis pathway. In this work, the detailed reaction mechanism of XB-catalyzed bromo-carbocyclization of <i>O</i>-phenyl cinnamyl ethers (<i>O</i>-PCE) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) is elucidated, and the relationship between the catalysts' structure and catalytic performance is established by density functional theory (DFT) calculations and corresponding property analysis methods. The reaction mechanism encompasses four key steps: formation of the halogen-bonded precomplexes, bromine transfer, cycloaddition, and proton transfer. Moreover, the present work reveals multiple catalytic pathways of bromo-carbocyclization. Except for the single-XB catalytic pathway, the reactant can be activated by dual XB at distinct carbonyl oxygens on both sides of DBDMH, bringing a product-involved dual XB concerted catalysis pathway. Through the dual-site-XB-network, the energy barriers of the reaction are further reduced. Additionally, the XBs between catalysts and the carbonyl oxygen on DBDMH induce the redistributions of charge densities of reactants, which stabilize the transition state and promote the reaction in the bromine transfer and proton transfer steps. With the enhanced XB bonds by different XB catalysts, the enhanced polarization effects facilitate the electrophilic attraction of the bromide anion and promote the bromine transfer substep. This work provides a theoretical perspective for the rational design of efficient XB catalysts for bromo-carbocyclization. Moreover, the newly proposed insights extend the application boundaries of noncovalent catalysis.