An integrated high throughput experimentation/predictive QSAR modeling approach to ansa-zirconocene catalysts for isotactic polypropylene

Compared to heterogenous Ziegler-Natta systems (ZNS), ansa-metallocene catalysts for the industrial production of isotactic polypropylene feature a higher cost-to-performance balance. In particular, the C2-symmetric bis(indenyl) ansa-zirconocenes disclosed in the 1990s are complex to prepare, less stereo-and/or regioselective than ZNS, and lose performance at practical application temperatures. The golden era of these complexes, though, was before High Throughput Experimentation (HTE) could contribute significantly to their evolution. Herein, we illustrate a Quantitative Structure-Activity Relationship (QSAR) model trained on a robust and highly accurate HTE database. The clear-box QSAR model utilizes, in particular, a limited number of chemically intuitive 3D geometric descriptors that screen various regions of space in and around the catalytic pocket in a modular way thus enabling to quantify individual substituent contributions. The main focus of the paper is on the methodology, which should be of rather broad applicability in molecular organometallic catalysis. Then again, it is worth emphasizing that the specific application reported here led us to identify in a comparatively short time novel zirconocene catalysts rivaling or even outperforming all previous homologues which strongly indicates that the metallocene story is not over yet.