Kevin McFadden’s research while affiliated with University of Utah and other places

The area of organic electrocatalysis has been growing in importance as many new transformations have been developed and previously known transformations are adapted to be accomplished electrochemically. As the field of synthetic organic electrochemistry emerges, it is becoming ever more important to study the mechanisms of these electrocatalytic reactions. Understanding the mechanics of the chemical processes and how they are coupled to the electrode is critical for continuing to expand the synthetic utility of electrocatalysis. Radical based hydrofunctionalization of alkenes through transition-metal catalyzed hydrogen atom transfer (MHAT) mechanisms is a proven, powerful mode of forming C−C, C−O, C−N and C−X bonds. In recent years, new asymmetric MHAT reactions have been enabled through electrocatalysis. The in situ generation of the key metal-hydride species plays a crucial role in both the kinetics and selectivity of the observed products. These high energy metal hydrides are too reactive and too short lived to be isolated, thus the oxidative mechanism leading to their formation is poorly understood. Here, we utilize a model catalytic cycle in which metal hydride formation is the rate determining step. Cyclic voltammetry enables us to extract the rate constant of hydride transfer. The differences in kinetic trends between catalysts and hydride donors indicate separate mechanisms of hydride transfer are operative for different classes of MHAT catalysts. Specific trends in ligand electronics, hydride donor sterics and hydricity for cobalt salen type catalysts allowed us to postulate a possible metal/ligand cooperative mechanism of hydride transfer. In summary, these studies represent a significant step towards understanding the homolytic reactivity of metal hydride species and will help enable the design of new electrosynthetic reactions involving radical intermediates.

Electrochemical organic synthesis shows promise for the sustainable synthesis of agrochemical and pharmaceutically relevant molecules. However, the complexity of integrating organic and electrochemical methods often leads to overlooked reaction parameters. For example, electrolyte salts are used to decrease resistivity of the electrochemical cell and are traditionally viewed as benign species in electrochemical systems. However, the electroorganic literature is filled with examples in which changing the identity of the electrolyte impacts the reaction selectivity significantly, implying that these ‘benign’ molecules have overlooked chemical contributions to reactivity, such as the stabilization of critical intermediates. Here, we explore the impact of electrolyte species on an important class of organic reactions: organic bond homolysis. In this reaction, a cage-paired radical is formed through the homolytic cleavage of a carbon bond, which then exists in a shell of solvent and solvated salts. This solvent-ion shell can stabilize this intermediate and allow for reversible bond homolysis. Such caged species are well-studied phenomena in metal-hydrogen atom transfer reactions and have been demonstrated to directly influence product selectivity in various organic reactions such as hydrogenation, isomerization, and dimerization. Here, we focus on how the lifetimes of cage-paired metal alkyl radical species are affected by common organic electrolytes and how this lifetime informs product selectivity. The lifetimes of these caged intermediates in various electrolyte conditions were examined using cyclic voltammetry, where titration studies were conducted to determine the rate of escape from the solvent-ion cage. This study provides insight into the role of common electrolyte salts on the stability of caged metal alkyl species and subsequent selectivity in organic synthetic reactions.

Malate is a key intermediate in the citric acid cycle, an enzymatic cascade that is central to cellular energy metabolism and that has been applied to make biofuel cells. To enable real-time sensing of malate levels, we have engineered a genetically encoded, protein-based fluorescent biosensor called Malon specifically responsive to malate by performing structure-based mutagenesis of the Cache-binding domain of the Citron GFP-based biosensor. Malon demonstrates high specificity and fluorescence activation in response to malate, and has been applied to monitor enzymatic reactions in vitro. Furthermore, we successfully incorporated Malon into redox polymer hydrogels and bacterial cells, enabling analysis of malate levels in these materials and living systems. These results show the potential for fluorescent biosensors in enzymatic cascade monitoring within biomaterials and present Malon as a novel tool for bioelectronic devices.