The Impact of Computational Uncertainties on the Enantioselectivity Predictions: A Microkinetic Modeling of Ketone Transfer Hydrogenation with a Noyori-type Mn-diamine Catalyst.

Annika M Krieger,Evgeny A Pidko

doi:10.1002/cctc.202100341

Abstract

Selectivity control is one of the most important functions of a catalyst. In asymmetric catalysis the enantiomeric excess (e.e.) is a property of major interest, with a lot of effort dedicated to developing the most enantioselective catalyst, understanding the origin of selectivity, and predicting stereoselectivity. Herein, we investigate the relationship between predicted selectivity and the uncertainties in the computed energetics of the catalytic reaction mechanism obtained by DFT calculations in a case study of catalytic asymmetric transfer hydrogenation (ATH) of ketones with an Mn‐diamine catalyst. Data obtained from our analysis of DFT data by microkinetic modeling is compared to results from experiment. We discuss the limitations of the conventional reductionist approach of e.e. estimation from assessing the enantiodetermining steps only. Our analysis shows that the energetics of other reaction steps in the reaction mechanism have a substantial impact on the predicted reaction selectivity. The uncertainty of DFT calculations within the commonly accepted energy ranges of chemical accuracy may reverse the predicted e.e. with the non‐enantiodetermining steps contributing to e.e. deviations of up to 25 %.

Highlights

Asymmetric reduction catalysis is a powerful tool for the production of chiral compounds
We investigate the relationship between predicted selectivity and the uncertainties in the computed energetics of the catalytic reaction mechanism obtained by Density functional theory (DFT) calculations in a case study of catalytic asymmetric transfer hydrogenation (ATH) of ketones with an Mn-diamine catalyst
Our analysis shows that the energetics of other reaction steps in the reaction mechanism have a substantial impact on the predicted reaction selectivity

Summary

Introduction

Asymmetric reduction catalysis is a powerful tool for the production of chiral compounds. The asymmetric transfer hydrogenation of ketones by transition metal catalysts has been studied and the catalytic mechanism has been addressed by numerous computational and experimental works.[31,35,36] In the last decade substantial efforts were put in the development of new catalysts based on earth-abundant elements. We employ a DFTbased microkinetic modeling to explore how accurate e.e. predictions can be, assuming the chemical accuracy of DFT calculations and taking a kinetic model of the complete catalytic cycle into account for a simple chiral Mn-diamine catalysts. Mn-diamine catalyst with reaction site NH1 and NH2 and the model reaction of acetophenone to phenylethanol heme Caption This model does not account for the kinetic nature of the enantiomeric excess and its potential variations during the reaction. The complex reaction network contributes to the e.e.’s that is a function of conversion due to the interplay of forward and backward reactions

Results and Discussion

Conclusion

Conflict of Interest