Double-boron heterocyclic carbenes: a computational study of Diels-Alder reactions

An aromatic boron-containing organic compound, C₂B₂H₂, with an unusual CC bond was experimentally synthesized in 2017. Here we investigate the structure and bonding nature of C₂B₂H₂ and its derivatives C₂B₂R₂ using DFT and VB theory. Although the CC bond in C₂B₂R₂ consists of a π bond and a charge-shift (CS) bond, C₂B₂F₂ has the lowest LUMO energy and its LUMO is similar to that of ethylene, suggesting that C₂B₂F₂ can be an ideal dienophile for the Diels-Alder reaction. Subsequently, the mechanism and stereoselectivity of the Diels-Alder reaction of C₂B₂F₂ with 5-substituted cyclopentadienes are studied. Computations demonstrate that these Diels-Alder reactions are feasible thermodynamically and kinetically. The stereoselectivity and distortion angles of C₂B₂R₂ exhibit linear correlations with the electronegativity difference between the two substituents bonded to the C(sp³) of cyclopentadiene, suggesting that the stereoselectivity of related Diels-Alder reaction products can be modulated by the substitution of cyclopentadiene. Considering the current interest in boron neutron capture therapy (BNCT), we design six BNCT drugs through the Diels-Alder reaction of C₂B₂F₂ with dienes containing peptide fragments. Thus, we demonstrate a new method for designing three-in-one BNCT drugs via the facile Diels-Alder reaction.