C−H bond functionalization is an important transformation of broad utility for chemical synthesis. Using transition metal catalysts, like cobalt, allows for the synthesis of new molecules from electron-rich arenes. This research reports the synthesis of 6-coordinated arene-chromium tricarbonyl complexes that are able to undergo cobalt-catalyzed C−H borylation. Furthermore, this work finds that these 6-coordinated complexes can catalytically compete with known reactive substrates, like fluoroarenes. These reactions can be used to synthesize new molecules from aromatic molecules with electron-withdrawing and electron-donating substituents, which has previously been proven very difficult. These new molecules have applications in the pharmaceutical, agriculture, and materials industries.

Lenacapavir, a novel drug for HIV, is administered as only a twice-yearly injectable, and it has shown to be 100% effective in clinical trials. However, its reliance on palladium catalysts to synthesize key fragments of lenacapavir contribute to its immense cost, thus presenting a significant barrier to accessing advanced HIV treatments. Expanding global access to lenacapavir has motivated replacement of palladium conditions with more sustainable and affordable earth-abundant transition metal catalysts such as nickel to substantially decrease the cost of synthesis. In particular, this thesis targets the Sonogashira C(sp)–C(sp2) coupling to synthesize Fragment A. Previous studies have shown bidentate N-donor ligands such as bipyridine to be effective in nickel-catalyzed Sonogashira cross-couplings; interest has thus been drawn to α-diimine (DI) ligands, due to their affordable synthesis and high modularity. This work explores the use of substituted DI ligands and well-defined nickel complexes for catalyzing a regioselective Sonogashira coupling on model bromopyridine substrates relevant to Fragment A. Well-defined nickel complexes — including bis ligand complexes, (MesDI)NiMe2, and (MesDI)Ni(η2-alkyne) complexes — were all synthesized and demonstrated catalytic competence, suggesting the presence of several potential pathways for entering the catalytic cycle. DI ligands therefore proved to be effective alternatives for nickel-catalyzed, regioselective Sonogashira couplings of model substrates applicable to improving the synthesis of lenacapavir.

Within catalysis, transition-metal complexes are powerful due to their versatility and robustness, where modification of the ligand or metal can tweak catalytic activity and pathways. Redox-active ligands such as PDI are attractive as they facilitate metal-ligand cooperation and stabilize the compound. Over the years, a variety of PDI ligands have been investigated, where altering its electronics and steric bulk can increase activity or suppress undesired reaction pathways. In particular, the Chirik group has demonstrated how increasing steric bulk drives selectivity and catalytic activity in (PDI)Fe for [2+2] cycloaddition. [2+2] cycloaddition generates cyclobutane derivatives, which are building blocks for natural product and petrochemicals. Previous work in the group demonstrated that increasing steric bulk in PDI suppresses the undesired β-H elimination pathway in [2+2] cycloaddition. Since the group has not explored PDI ligands bulkier than iPrPDI , this work describes the synthesis of sBuPDI and i-PentPDI ligands and their metalation onto Fe. The reduced (PDI)Fe complexes were found to have lower catalytic activity than the parent (iPrPDI)Fe precatalyst in [2+2] cycloadditions.

There is an increasing need for sp3 carbons in industrial and pharmaceutical sectors. A higher sp3 content can be achieved via hydrogenation reactions that require catalysts with high chemo- and enantioselectivities, typically based on precious metals. Previous work in the Chirik group has developed pre-catalysts of oxazoline imino(pyridine) (OIP) and pyridine (diimine) (PDI) ligand frameworks based on the earth-abundant metal molybdenum. This work aims to integrate features of both PDI and OIP catalysts into the PDI ligand framework for the asymmetric hydrogenation of naphthalene. A pathway for the ligand synthesis of C1-symmetric PDI ligand was developed. C1- and C2-symmetric PDI(Mo)COD pre-catalysts were synthesized, and their catalytic activity was evaluated for 2,6- substituted naphthalene. Results revealed that the C1- and C2-symmetric 4-tBu-((S)-Cy,MePDI)Mo(COD) were active hydrogenation catalysts for 2,6-dimethylnaphthalene, and selective for the partially reduced product. While the C2-symmetric catalyst induced no enantioselectivity, the C1-symmetric 4-tBu-((S)-Cy,MePDI)Mo(COD) achieved an enantiomeric excess of 13%. Preliminary work has been done on developing C1-symmetric PDI ligands substituted with chiral anilines to increase enantioselectivity.

Suzuki-Miyaura cross-coupling is one of the most important named chemical reactions used in industrial synthesis. Although palladium catalysts are most often used for these reactions, catalysts that instead use first-row metals are of interest in part because they may offer complementary reactivity to the shortcomings of palladium catalysts, in addition to being more sustainable, lower cost, and usually less toxic. This work highlights nickel catalysts bearing phenoxyimine (FI) and phenoxythiazoline (FTz) ligands for C(sp$2$)–C(sp$3$) cross-coupling reactions, specifically expanding the scope of the Chirik group’s previously reported nickel-catalyzed Suzuki-Miyaura cross-coupling method from boronic acids and boronic neopentyl glycol esters to boronic pinacol esters. These substrates are of particular interest given their ease of installment on highly functionalized scaffolds via Miyaura borylation. Reaction conditions are optimized for this specific type of reaction, the reactivity of FI and FTz ligands are compared, and the expanded nucleophile scope is briefly investigated. The results herein demonstrate the applications these nickel complexes have toward C(sp$2$)–C(sp$3$) Suzuki-Miyaura cross-coupling and establish a method that can be used to cross-couple boronic pinacol esters.

Plastics are used ubiquitously throughout modern society, but present methods of recycling are insufficient to address plastic waste accumulation, and the use of monomers sourced primarily from petrochemicals contributes to our reliance on fossil fuels. Developing chemically recyclable polymers to reduce the demand for petroleum-derived raw materials and polymer compatibilizers to improve the efficacy of plastic recycling have emerged as attractive strategies to mitigate these concerns. The Chirik Group has developed iron catalysts that selectively generate (1,n’-divinyl)oligocyclobutane (DVOCB), a chemically recyclable polyolefin architecture derived from butadiene, and 1,6-dimethyl-1,5-cyclooctadiene (1,6-DMCOD), a monomer derived from isoprene that is used to synthesize a polyethylene-polypropylene compatibilizer. Importantly, both butadiene and isoprene are abundant and inexpensive hydrocarbon feedstocks with emerging bio-derived routes. However, the state-of-the-art iron catalysts developed for DVOCB (de)oligomerization and 1,6-DMCOD synthesis are highly air-sensitive, rendering industrial application challenging. Moreover, the iron catalyst used for 1,6-DMCOD synthesis also generates minor mono- and di-substituted olefin side products, which require additional purification steps to remove. To address these limitations, nickel and iron catalysts were explored in this work. Prior studies of N-heterocyclic carbene (NHC)-supported nickel complexes acting as robust DVOCB deoligomerization catalysts were continued through the exploration of electron-deficient NHCs and commercially available phosphines. The performance of thermally robust (NHC)Ni complexes as [4+4] cycloaddition catalysts was also studied and demonstrated to be unselective for 1,6-DMCOD synthesis. Finally, ligand modifications were made to the state-of-the-art Fe system to enhance selectivity for the [4+4] cyclodimerization of isoprene.