Computational Insights into Endo/Exo Selectivity of Diels--Alder Reaction in Explicit Solvent at ab Initio Quantum Mechanical/Molecular Mechanical Level

The microscopic insight into the endo/exo stereoselectivity of the Diels–Alder (DA) reaction between cyclopentadiene and methyl vinyl ketone (MVK) has posed a challenge to the computational chemists, which requires an accurate free-energy (FE) landscape. Although ab initio (ai) quantum mechanical/molecular mechanical (QM/MM) calculations are capable of providing accurate conformation energies, they are far too expensive for free-energy calculations, in which large-scale sampling in the phase space is always indispensable. Recently, on the basis of the idea of reference-potential methods, a new approach termed MBAR+wTP method was proposed by us (Li; J. Chem. Theory Comput. 2018, 14, 5583) for the calculations of ai QM/MM FE profiles with a much less computational expense. In this work, we applied this method to investigate the endo/exo stereoselectivity of the Diels–Alder (DA) reaction at B3LYP/MM level and the results indicate that this method can yield more accurate activation free energies than the semi...