The field of catalysis is driven forward by the development of new paradigms for rapid, selective transformations of new and existing feedstocks into valuable products. Underpinning these developments are fundamental descriptors of mechanism, the atomic and electronic details that govern chemical reactivity. Quantum chemical simulation provides direct access at this level of information, but such simulation often comes with surprisingly high costs in terms of computational time and human effort — costs that our research is working to eliminate.

New Methods for Automated Mechanism Searching

Research in the Zimmerman group seeks to revolutionize the characterization of mechanism using automated methods that are fast, reliable, and require minimal human effort. Techniques such as fast string methods for locating reaction paths can be combined with automatic elementary step exploration to yield quantitative comparisons of competing reaction paths. The methods can be operated as “single-ended,” where reactivity is explored without knowing the final destination, or “double-ended,” where the product is already known beforehand.

ZStruct, a reaction-finding tool, was applied to investigate the mechanisms for high-valent palladium C(sp3)-N bond forming reductive elimination. Two resulting pathways were identified, including a non-intuitive, concerted, SN2-like reductive elimination pathway proceeding through an oxygen-bound sulfonamide complex (shown in the animation).  These results indicate that consideration of both pathways is necessary to effectively model C(sp3)-N reductive elimination.

In a single-ended reactivity search, systematic automated investigation of pathways will locate reaction paths that would not have been found by manual investigation, and this means the predictive value can be high. Much of the “human bias” factor is removed from the simulations, leading to possibilities that have never been conceived. Significant amounts of effort are currently being applied to creation of these tools, with the first algorithm being detailed in references 2 and 4 below.

Applications of the Growing String Method

We have applied the growing string method for cwalk elucidating the mechanism for off-cycle nickel-catalyzed C-H abstraction. Under conditions that utilize cyclooctadiene (COD) based precataylsts in nickel-catalyzed C-H functionalization reactions, there is potential for the C-H bond to be broken and directly transferred to COD. Iterative chain walking events ultimately leads to off-cycle resting states that inhibit catalysis. It was found that adapting the catalyst to remove COD produces much more efficient catalytic reactions.

New Methods for Catalyst Optimization

When a catalyst operating mechanism is reasonably well-understood, the limiting factors for catalysis can be targeted for enhancement. New techniques are under development which will optimize specific catalyst properties using quantum chemical simulation. Stay tuned for more information as these exciting new opportunities for catalyst design are created and tested on challenging problems in renewable energy and polymerization catalysis.

 Recent catalysis related publications:

1. Y. Y. Khomutnik, A. J. Argüelles, G. A. Winschel, Z. Sun, P. M. Zimmerman,* P. Nagorny,* “Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions,” Journal of the American Chemical Society, published online, DOI: 10.1021/jacs.5b12528.

2. A. J. Nett, W. Zhao, P. M. Zimmerman, J. Montgomery, “Highly Active Nickel Catalysts for C−H Functionalization Identified through Analysis of Off-Cycle Intermediates,” Journal of the American Chemical Society, 137, 7636, 7639 (2015).

3. P. M. Zimmerman, “Navigating Molecular Space for Reaction Mechanisms: An Efficient, Automated Procedures,” Molecular Simulation, 41, 43-54 (2014).

4. Z. Sun, G. A. Winschel, P. M. Zimmerman, P. Nagorny, “Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies,” Angewandte Chemie International Edition, 53, 11194-11198 (2014).

5. P. M. Zimmerman, “Automated discovery of chemically reasonable elementary reaction steps,” Journal of Computational Chemistry, 34(16), 1385-1392 (2013).