Enantioselective palladium-catalyzed hydrosilylation of styrene: Influence of electronic and steric effects on enantioselectivity and catalyst design via hybrid QM/MM molecular dynamics simulations

The factors determining the enantioselectivity of the palladium-catalyzed hydrosilylation of styrene have been rationalized by performing mixed QM/MM Car-Parrinello molecular dynamics simulations with styrene and 4-(dimethylamino)styrene as substrates. Our results demonstrate that the eta(3)-benzylic intermediate plays a crucial role in the stereoselectivity of the reaction. The relative thermodynamic stabilities (Delta E approximate to 1-2 kcal/mol) of the endo and exo eta(3) forms of the benzylic intermediates, precursors of the two enantiomeric products, are inverted as a function of the electron-releasing or -withdrawing nature of the para substituent of the substrate, and this trend holds also for the transition state of the reductive elimination step (the enantioselectivity-determining step). An electronic and structural characterization of the benzylic diasteroisomers shows that steric effects also play an important role in the inversion of the relative thermodynamic stability of the two allylic diasteroisomers. An analysis of the charge distribution of the free benzyl radical and a computational design of the catalyst suggest that the extent of the chiral induction may be moderately affected by the electronic properties of the substrate, but the sense is mainly dominated by steric effects of both the substrate and the ligands. Finally, we provide suggestions that may increase the observed enantiomeric excess (ee) of the reaction.