Abstract: This dissertation will discuss advancements made toward understanding the intrinsic reactivity of nitrogenous ligands in nickel-catalyzed cross-electrophile coupling, as well as their impacts on reaction selectivities.
Chapter 1 will introduce cross-electrophile coupling, highlight the importance of ligands in promoting diverse elementary steps, and discuss strategies to search for, understand, and improve ligand architecture.
Chapter 2 describes our initial investigation utilizing descriptors from a diverse set of ligands and ligand-like molecules to predict reaction yield and selectivity. This investigation provided critical insight into experimental design, construction of a training set, and determining project outcomes. The results of these efforts informed our studies that are detailed in successive chapters.
Chapter 3 summarizes the application of statistical methods to develop a model for selectivity in bipyridine-nickel-catalyzed cross-electrophile coupling. The resulting model was used to rationalize experimental outcomes, develop mechanistic insight, and design improved ligands in silico.
Chapter 4 summarizes initial insights into the relationships between the structure of other classes of heterocycle-based L2 dinitrogen ligands and their corresponding experimental outcomes. These investigations provide a basis for understanding the performance of these ligands and expands on the insights described in Chapter 3. A plan for ongoing research informed by these results is proposed.
Chapter 5 describes additional computationally informed projects that were undertaken by the author. These projects utilize computed catalyst structures and energies to rationalize the impact of ligand binding on the reactivity of novel 2,2’-bipyridine-6-carbonitrile ligands, as well as the relationship of ligand structure to selectivity in decarbonylative cross-electrophile coupling.
Abstract: The capture of carbon-centered radicals at a nickel(II) center is commonly featured in recent cross-coupling and metallaphotoredox catalytic reactions. Despite its widespread application in catalysis, this fundamental step lacks experimental characterization. This report portrays radical capture at catalytically relevant nickel(II) centers from several aspects, including the structure-activity relationships of the ligands, the mechanism, the kinetics, and the stereoselectivity. Spectroscopic data provide evidence for the formation of a nickel(III) intermediate. Strikingly different reactivity between nickel-aryl and nickel-alkyl complexes implies different rate-determining steps for C(sp3)–C(sp3) and C(sp2)–C(sp3) bond formation. Kinetic data benchmark the capture rates on the scale of 10[7] M?1s?1 and 10[6] M?1s?1 for primary and secondary radicals, respectively. Overall, the activation energy is higher than that of previous computational estimations. Finally, stoichiometric experiments with well-defined chiral nickel complexes demonstrate that the radical trapping step can confer diastereoselectivity and enantioselectivity with a drastic ligand effect.
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With palladium diacetate; potassium carbonate; at 120℃; for 48h;Inert atmosphere;
General procedure: 2-Iodopyrazine (5.00 g, 24.3 mmol), PdII(OAc)2 (34 mg, 0.151 mmol), K2CO3 (3.4 g, 24.6 mmol) and poly(ethylene glycol) (Mw 4000, 24.0 g) were combined in an argon-purged flask. The mixture was gradually heated to 120 C and the temperature maintained for 48 h with stirring. The mixture was cooled to ca. 80 C and warm water (30 mL) was added to prevent solidification. On cooling to room temperature, further water (100 mL) was added and the suspension exhaustively extracted with ethyl acetate. The combined extracts were washed once with saturated aqueous Na2S2O3 and then thrice with brine. The organic layer was dried over MgSO4 and solvent removed under vacuum. The residue was triturated with n-pentane and the white crystalline solid filtered off, washed with n-pentane and dried. Yield: 1.35 g (70%).
52%
2.2 Synthesis of 4,4'-bis(trifluoromethyl)-2,2'-bipyridine 2-Bromo-4-trifluoromethyl pyridine (1.2 g, 5.31 mmol) was placed in a round bottom flask with 7.14 g of activated copper bronze. The reaction flask was then flushed with N2 and a reflux condenser was affixed. The reaction was then heated to 190 C for 16 h. The reaction was then cooled to room temperature and the ligand extracted with acetone and chloroform (?100 mL). The organic fraction was then extracted with 1.2 N HCl. Once the aq. fraction turned blue, the organic fraction was extracted then evaporated to afford a yellow oil. The ligand was then purified by vacuum sublimation (52% yield). Spectroscopic data matched literature values [12] .
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