Automated de Novo Design of Olefin Metathesis Catalysts: Computational and Experimental Analysis of a Simple Thermodynamic Design Criterion.

Methods for computational de novo design of inorganic molecules have paved the way for automated design of homogeneous catalysts. Such studies have so far relied on correlation-based prediction models as fitness functions (figures of merit), but the soundness of these approaches has yet to be tested by experimental verification of de novo-designed catalysts. Here, a previously developed criterion for the optimization of dative ligands L in ruthenium-based olefin metathesis catalysts RuCl(L)(L')(═CHAr), where Ar is an aryl group and L' is a phosphine ligand dissociating to activate the catalyst, was used in de novo design experiments. These experiments predicted catalysts bearing an N-heterocyclic carbene (L = ) substituted by two N-bound mesityls and two -butyl groups at the imidazolidin-2-ylidene backbone to be promising. Whereas the phosphine-stabilized precursor assumed by the prediction model could not be made, a pyridine-stabilized ruthenium alkylidene complex () bearing carbene was less active than a known leading pyridine-stabilized Grubbs-type catalyst (, L = HIMes). A density functional theory-based analysis showed that the unsubstituted metallacyclobutane (MCB) intermediate generated in the presence of ethylene is the likely resting state of both and . Whereas the design criterion via its correlation between the stability of the MCB and the rate-determining barrier indeed seeks to stabilize the MCB, it relies on RuCl(L)(L')(═CH) adducts as resting states. The change in resting state explains the discrepancy between the prediction and the actual performance of catalyst . To avoid such discrepancies and better address the multifaceted challenges of predicting catalytic performance, future de novo catalyst design studies should explore and test design criteria incorporating information from more than a single relative energy or intermediate.