Anat Milo1, Andrew J Neel2, F Dean Toste3, Matthew S Sigman4. 1. Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA. 2. Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California, Berkeley, CA 94720, USA. 3. Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California, Berkeley, CA 94720, USA. sigman@chem.utah.edu fdtoste@berkeley.edu. 4. Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA. sigman@chem.utah.edu fdtoste@berkeley.edu.
Abstract
Knowledge of chemical reaction mechanisms can facilitate catalyst optimization, but extracting that knowledge from a complex system is often challenging. Here, we present a data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction. As a validating case study, we selected an intramolecular dehydrogenative C-N coupling reaction, catalyzed by chiral phosphoric acid derivatives, in which catalyst-substrate association involves weak, noncovalent interactions. Little was previously understood regarding the structural origin of enantioselectivity in this system. Catalyst and substrate substituent effects were probed by means of systematic physical organic trend analysis. Plausible interactions between the substrate and catalyst that govern enantioselectivity were identified and supported experimentally, indicating that such an approach can afford an efficient means of leveraging mechanistic insight so as to optimize catalyst design.
Knowledge of chemical reaction mechanisms can facilitate catalyst optimization, but extracting that knowledge from a complex system is often challenging. Here, we present a data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction. As a validating case study, we selected an intramolecular depanclass="Chemical">hydrogenative C-N coupling reaction, catalyzed by chiral class="Chemical">pan class="Chemical">phosphoric acid derivatives, in which catalyst-substrate association involves weak, noncovalent interactions. Little was previously understood regarding the structural origin of enantioselectivity in this system. Catalyst and substrate substituent effects were probed by means of systematic physical organic trend analysis. Plausible interactions between the substrate and catalyst that govern enantioselectivity were identified and supported experimentally, indicating that such an approach can afford an efficient means of leveraging mechanistic insight so as to optimize catalyst design.
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