Ligand Design for Energy Conversion and Storage Applications

The contents of this thesis are divided into two topics that fall under the umbrella of energy conversion and storage. The first section focuses on tuning the standard reduction potential of the Fe3+/2+ redox couple with the aid of nitrogen-based ligands, in pursuit of an all-iron, water-based redox-flow battery. Also included is the synthesis and characterization of iron coordination complexes with redox-active ligands featuring quinone/hydroquinone functional groups. This study aims to exploit the potential of this system incorporating Fe3+/2+ and a redox non-innocent ligand for application in single-component redox-flow batteries. The second portion of the thesis targets homogeneous single-site catalysts for the electrochemical reduction of CO2. The ability of nickel and iron complexes incorporating a redox non-innocent bis(triazapentadienyl) ligand to promote this transformation was investigated. The nickel complex was identified as more promising and infrared spectroelectrochemistry was used to determine the fate of the metal during controlled potential electrolysis, as well as to identify the extent to which a large excess of ligand-based redox behavior impacts electrocatalytic CO2 reduction. The synthesis and characterization of other ligand scaffolds based on tetradentate bis(carbene) macrocycles and porphyrinoids is discussed, with alterations to the parent framework aimed at increasing solubility and stability during metal complexation. Also reported are efforts tailored towards the synthesis of ligands based on a bipyridine central donor with flanking phosphine chalcogenides. The phosphine oxide generated iron, nickel and rhenium complexes while the phosphine sulfide analog proved to be a surprisingly incompetent ligand

Nickel as a Lewis Base in a T‐Shaped Nickel(0) Germylene Complex Incorporating a Flexible Bis(NHC) Ligand

Flexible, chelating bis(NHC) ligand 2, able to accommodate both cis- and trans-coordination modes, was used to synthesize (2)Ni(η 2 -cod), 3. In reaction with GeCl2, this produced (2)NiGeCl2, 4, featuring a T-shaped Ni(0) and a pyramidal Ge center. Complex 4 could also be prepared from [(2)GeCl]Cl, 5, and Ni(cod)2, in a reaction that formally involved Ni-Ge transmetalation, followed by coordination of the extruded GeCl2 moiety to Ni. A computational analysis showed that 4 possesses considerable multiconfigurational character and the Ni→Ge bond is formed through σ-donation from the Ni 4s, 4p, and 3d orbitals to Ge. (NHC)2Ni(cod) complexes 9 and 10, as well as (NHC)2GeCl2 derivative 11, incorporating ligands that cannot accommodate a wide bite angle, failed to produce isolable Ni-Ge complexes. The isolation of (2)Ni(η 2 -Py), 12, provides further evidence for the reluctance of the (2)Ni(0) fragment to act as a σLewis acid.peerReviewe

Ligand-Centered Electrochemical Processes Enable CO2 Reduction with a Nickel Bis(triazapentadienyl) Complex

We report the synthesis of Ni(TAPPy)2 (TAPPy = 1,3,5-triazapentadienyl-2,4-bis(2-pyridyl)) and its reactivity with CO2 under reducing conditions. Electrochemical reduction of Ni(TAPPy)2 under inert gas reveals that the complex accommodates up to two additional electrons, with DFT calculations indicating that electron density is delocalized almost exclusively onto the TAPPy ligand framework. The singly reduced product [K(crypt)][Ni(TAPPy)2] (crypt = 2.2.2-cryptand) has been synthesized, and its EPR data is consistent with having ligand-based radical anion character. Controlled potential electrolysis experiments reveal that reduced Ni(TAPPy)2 converts CO2 to form CO; however, spectroscopic and computational data indicate that deactivation readily occurs to form Ni(L)(CO)n compounds, CO32-, and carboxylated (RCOO-) ligand decomposition products. This study highlights that redox activity at the ligand can play an important role during the reduction of CO2 using transition metal complexes

Divergent Kinetics Differentiate the Mechanism of Action of Two HDAC Inhibitors

Histone deacetylases (HDACs) play diverse roles in many diseases including cancer, sarcopenia, and Alzheimer’s. Different isoforms of HDACs appear to play disparate roles in the cell and are associated with specific diseases; as such, a substantial effort has been made to develop isoform-selective HDAC inhibitors. Our group focused on developing HDAC1/HDAC2-specific inhibitors as a cancer therapeutic. In the course of characterizing the mechanism of inhibition of a novel HDAC1/2-selective inhibitor, it was determined that it did not exhibit classical Michaelis–Menten kinetic behavior; this result is in contrast to the seminal HDAC inhibitor SAHA. Enzymatic assays, along with a newly developed binding assay, were used to determine the rates of binding and the affinities of both the HDAC1/2-selective inhibitor and SAHA. The mechanism of action studies identified a potential conformational change required for optimal binding by the selective inhibitor. A model of this putative conformational change is proposed

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets