Iridium-PHOX-Mediated Alkene Hydrogenation: Isomerization Influences the Stereochemical Outcome

Recent experimental studies of iridium-phosphinooxazoline-mediated
alkene hydrogenation indicated two dihydride species as resting states,
with the minor isomer assumed to give rise to the major product enantiomer
[Gruber and Pfaltz, Angew. Chem. Int. Ed. 2014, 53, 1896]. B3LYP-D2 calculations confirm the two
dihydride intermediates as resting states but show that these species
do not give rise to the lowest-lying hydrogenation barriers. Instead,
both species prefer to isomerize to different intermediates prior
to hydrogenation. The computed enantiomeric excess (ee) at 298 K is
in excellent agreement with experiment. The calculations further show
an increased barrier for isomerization between the dihydride species
at lower temperature. Numerical simulations of the overall reaction
kinetics indicate that this can explain the reduced enantioselectivity
observed experimentally at 233 K. Analysis of the selectivity-determining
interactions identifies strong C-H/π interactions between the
oxazoline substituents and the alkene. On the basis of the insights
obtained, a rational redesign of the catalyst is suggested, resulting
in an improved ee in silico. Additional benchmark studies on different
experimental barriers and reaction energies for iridium complexes
confirm the suitability of the employed computational protocol.