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

An aromatic boron-containing organic compound, C₂B₂H₂, with an unusual CC 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 CC 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.