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.