A Quantum-Guided Molecular Mechanics Force Field for the Ferrocene Scaffold

Abstract

Ferrocene derivatives have a wide range of applications, including as ligands in asymmetric catalysis, due to their chemical stability, rigid backbone, steric bulk, and ability to encode stereochemical information via planar chirality. Unfortunately, few of the available molecular mechanics force fields incorporate parameters for the accurate study of this important building block. Here, we present a MM3* force field for ferrocenyl ligands, which was generated using the quantum-guided molecular mechanics (Q2MM) method. Detailed validation by comparison to DFT calculations and crystal structures demonstrates the accuracy of the parameters and uncovers the physical origin of deviations through excess energy analysis. Combining the ferrocene force field with a force field for Pd–allyl complexes and comparing the crystal structures shows the compatibility with previously developed MM3* force fields. Finally, the ferrocene force field was combined with a previously published transition-state force field to predict the stereochemical outcomes of the aminations of Pd–allyl complexes with different amines and different chiral ferrocenyl ligands, with an R 2 of ∼0.91 over 10 examples.

Paving the road towards automated homogeneous catalyst design

“…Virtual chemist, an approach by Patrascu et al., was specifically designed to empower experimental chemists with minimal computational chemistry knowledge [106] . This method combines Quantum‐guided Molecular Mechanics (Q2MM) and molecular mechanics force field (MM3 FF) methods to model the transition states [120,121] . This approach enables bench chemists to virtually screen asymmetric reactions and make predictions about potential catalysts before conducting laboratory experiments.…”

“…[106] This method combines Quantum-guided Molecular Mechanics (Q2MM) and molecular mechanics force field (MM3 FF) methods to model the transition states. [120,121] This approach enables bench chemists to virtually screen asymmetric reactions and make predictions about potential catalysts before conducting laboratory experiments. The study presents a significant advancement in the field of computational catalyst design through the development of a comprehensive virtual laboratory framework.…”

Interplay of Computation and Experiment in Enantioselective Catalysis: Rationalization, Prediction, and─Correction?

“…As outlined in more detail below, Q2MM automates the process of the fitting of a reaction specific force field (FF) of arbitrary functional form to the results of appropriate electronic structure calculations by minimizing an objective function χ 2 . Although Q2MM can also generate FFs for stable molecules, 87 it is most often used to generate transition-state force fields (TSFFs). 88 The Q2MM results are utilized in the Catalyst Virtual Screening (CatVS) method 89 to generate stereoselectivity predictions (see Figure 4).…”