Chapter One describes the computational study of the asymmetric arylation of propargylic electrophiles. While previous mechanistic experiments have verified the general scheme of the catalytic cycle, it was still not known what the enantiodetermining step is, or how factors of the ligand and substrate influence reactivity. To answer these questions, a computational study to emulate the entire catalytic cycle was performed. It was determined that radical addition to the nickel catalyst was likely the enantiodetermining step. While the standard substrate and ligand combinations result was well predicted, the computational method was not widely applicable to different ligands. This implies that the catalytic cycle may not go through a discrete radical capture and reductive elimination step, but instead a more concerted process may be operating.
\r\n\r\nChapter Two details the development of the asymmetric cross-coupling between tertiary nucleophiles and secondary electrophiles. Specifically, \u03b1-zincated benzylic nitriles are asymmetrically coupling with secondary alkyl iodides under the influence of a nickel catalyst and iminopyrox ligand. This study represents the first report of such a ligand being use for any asymmetric nickel-catalyzed cross-couplings.
\r\n\r\nChapter Three describes computational work on three separate projects published by coworkers in the Fu lab.
\r\n1) The first section details work on the nickel-catalyzed asymmetric coupling of enynes with secondary racemic electrophiles to accomplish for the first time the simultaneous control of axial and point chirality. The computational work probed the possible steps of rearrangement of the putative nickel-propargyl species into nickel allenyl species, as well as rationalized the different reactivity of the catalyst towards different electrophiles.
\r\n2) The second project was investigations into the photocatalytic coupling of secondary and tertiary electrophiles with secondary amines by copper and a dual-ligand system. The computations shed light on possible C\u2014N coupling mechanisms, as well as rationalized the differing photoactivity of the two CuI complexes present in the system.
\r\n3) The final work supported mechanistic studies into the photocatalytic asymmetric azidation of \u03b1-bromoamides by a copper-phosphine complex. DFT studies were performed to predict EPR spectra which were used to disambiguate the possible CuII species present in solution.
The formation of carbon-nitrogen (C\u2013N) bonds is crucial in organic chemistry due to the importance of nitrogen-containing functional groups. While traditional nucleophilic substitution reactions, such as SN1, SN2, and SNAr, are limited in scope and efficiency, transition metal-catalyzed versions of these reactions, particularly involving copper, offer a more versatile approach by activating electrophiles and facilitating C\u2013N bond formation via oxidative addition and reductive elimination.
\r\n\r\nCopper-catalyzed C\u2013N couplings have been extensively developed but are primarily effective for aryl electrophiles rather than alkyl electrophiles due to the need for thermal activation, which often leads to undesired side reactions in alkyl electrophiles. The development of photoinduced copper-catalyzed reactions by Fu and Peters addresses these challenges, enabling the activation of alkyl electrophiles without thermal activation.
\r\n\r\nOver the past decade, the Fu group has focused on expanding the scope of this novel approach. The research detailed in this thesis focuses on developing photoinduced copper-catalyzed C\u2013N coupling reactions for more challenging substrates, such as sterically hindered alkyl electrophiles and amines.
\r\n\r\nChapter 2 discusses the photoinduced, enantio-convergent coupling of racemic tertiary alkyl electrophiles with aniline nucleophiles, catalyzed by bisphosphine-copper complexes. The mechanism of this reaction was elucidated using various tools, identifying key copper-based intermediates, including a chiral copper(II)\u2013anilido complex that couples with a tertiary organic radical to form the C\u2013N bond with good enantioselectivity.
\r\n\r\nChapter 3 presents the photoinduced, copper-catalyzed coupling of secondary alkyl amines with secondary or tertiary alkyl bromides to synthesize N-tertiary alkyl amines under mild conditions. This novel reaction provides unique stereoselectivity and compatibility with strained electrophiles, contributing valuable methodologies to the synthesis of bioisosteres and other complex amine structures.
\r\n\r\nOverall, this work broadens the understanding and application of photoinduced copper-catalyzed reactions, offering new pathways for the synthesis of sterically hindered amines.
", "doi": "10.7907/1008-m865", "publication_date": "2025", "thesis_type": "phd", "thesis_year": "2025" }, { "id": "thesis:16385", "collection": "thesis", "collection_id": "16385", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05152024-205420698", "type": "thesis", "title": "Novel Reactivity and Applications of Transition Metal-Catalyzed Nucleophilic Substitution Reactions", "author": [ { "family_name": "Tong", "given_name": "Xiaoyu", "orcid": "0000-0002-1343-6335", "clpid": "Tong-Xiaoyu" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "For more than 20 years, the Fu lab has explored the use of transition metal catalysts to enable novel nucleophilic substitution reactions. However, deficiencies in both fundamental reactivity and useful applications persist in this area. The research detailed in this thesis focuses on the development of reactivity and applications of transition metal-catalyzed nucleophilic substitution reactions.", "doi": "10.7907/nqkk-2x98", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:14428", "collection": "thesis", "collection_id": "14428", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11182021-220809412", "primary_object_url": { "basename": "dfreas_thesis_final.pdf", "content": "final", "filesize": 8999194, "license": "other", "mime_type": "application/pdf", "url": "/14428/1/dfreas_thesis_final.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "The Synthesis of Diverse Families of Organic Compounds via Nickel-Catalyzed Nucleophilic Substitution Reactions", "author": [ { "family_name": "Freas", "given_name": "Dylan Joshua", "orcid": "0000-0003-0611-7907", "clpid": "Freas-Dylan-Joshua" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "orcid": "0000-0001-8244-9300", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Agapie", "given_name": "Theodor", "orcid": "0000-0002-9692-7614", "clpid": "Agapie-T" }, { "family_name": "Fu", "given_name": "Gregory C.", "orcid": "0000-0002-0927-680X", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Transition metal-catalyzed cross-coupling has provided an exceptionally powerful approach to carbon\u2013carbon bond formation, allowing chemists to solve a number of important problems in organic synthesis. However, by the early 2000s, its application to the formation of alkyl\u2013alkyl bonds had been limited by the slow oxidative addition of palladium catalysts toward alkyl halides and the tendency of transition-metal-alkyls to undergo \u03b2-hydride elimination. Since then, complexes based on nickel, an earth-abundant metal, have emerged as efficient catalysts for the nucleophilic substitution of alkyl electrophiles. The propensity for nickel to access a range of oxidation states allows it to react via one-electron pathways to generate radical intermediates, opening the door to couplings of sterically-hindered electrophiles and offering a ready mechanism for enantioconvergence.
\r\n\r\nOur group has applied nickel catalysts to substitution reactions of activated and unactivated 2o and 3o alkyl electrophiles by carbon\u2013 as well as by heteroatom-based nucleophiles, including a number of enantioconvergent processes. However, given the enormous range of conceivable coupling partners, many interesting challenges have yet to be addressed. The application of nickel-catalyzed substitution reactions to the synthesis of diverse families of compounds, particularly those with frequent uses in organic synthesis and pharmaceutical science, is described in this thesis. While reaction development is the primary focus of this work, a variety of synthetic applications and mechanistic investigations are also detailed within.
\r\n\r\nChapter 2 describes two methods for the catalytic enantioconvergent synthesis of amines, which involve the coupling of an alkylzinc reagent with a racemic electrophile (specifically, an \u03b1-phthalimido alkyl chloride and an N-hydroxyphthalimide ester of a protected \u03b1-amino acid). A one-pot variant of this transformation is possible, enabling the efficient enantioselective synthesis of a range of interesting target molecules. Several mechanistic insights are also detailed.
\r\n\r\nChapter 3 outlines the nickel-catalyzed alkylation of racemic \u03b1-haloglycine derivatives, a class of electrophile previously unemployed in metal-catalyzed asymmetric cross-coupling reactions, with alkylzinc reagents to generate protected unnatural \u03b1-amino acids. This method is applied to the generation of several enantioenriched unnatural \u03b1-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.
\r\n\r\nChapter 4 details the development of a nickel-catalyzed cross-coupling for the asymmetric synthesis of protected thiols. The synthesis of an N-hydroxyphthalimide ester containing a geminal thioester (a previously unreported class of molecule with no applications to cross-coupling) is described, along with its reactivity toward alkylzinc reagents and other classes of organometallic nucleophiles.
\r\n\r\nChapter 5 examines the ability of nickel to catalyze the nucleophilic fluorination of unactivated alkyl halides, a transformation whose application to the synthesis of alkyl fluorides has been impeded by the low nucleophilicity and high basicity of fluoride. The reactivities of unactivated 1o, 2o, and 3o alkyl bromides, as well as several preliminary mechanistic investigations, are presented.
", "doi": "10.7907/e76h-vh27", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:11516", "collection": "thesis", "collection_id": "11516", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05142019-145414091", "type": "thesis", "title": "Copper and Nickel Catalysis for the Construction of Novel C\u2212N and C\u2212C Bonds", "author": [ { "family_name": "Matier", "given_name": "Carson Douglas", "orcid": "0000-0002-1618-7944", "clpid": "Matier-Carson-Douglas" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "First-row transition-metals such as nickel and copper have revolutionized cross-coupling chemistry. Their propensity to form radical intermediates from alkyl electrophiles has greatly expanded the scope of traditional cross-coupling reactions. Alkyl radicals can be recaptured by a chiral transition-metal catalyst allowing for enantioselective bond formation. In general, alkyl radicals rapidly epimerize, and thus both enantiomers of a racemic mixture of an alkyl electrophile can be processed into the same enantiomer of product, rendering the overall process enantioconvergent. Herein, the development of basic bond constructions and the development of asymmetric reactions leveraging alkyl radical intermediates for carbon-nitrogen and carbon-carbon bond formations are discussed. Reaction development is the primary focus of this work, though mechanistic insights discovered along the way are also detailed within.
\r\n\r\nChapter 2 describes the development of an enantioconvergent alkylation of amine nucleophiles with alkyl electrophiles. Carbazole and indole derivatives are employed as nucleophiles to undergo copper-catalyzed cross-coupling with tertiary \u03b1-chloroamide electrophiles under visible light irradiation. Reaction optimization, scope of reactivity, inorganic synthesis, and mechanistic insights are described within.
\r\n\r\nChapter 3 details the development of a non-asymmetric copper-catalyzed alkylation of aliphatic amines with unactivated alkyl electrophiles under visible light irradiation. The development of a novel catalytic system to circumvent the issues with the photophysical properties of aliphatic amine-copper complexes is discussed. Scope of reactivity and mechanistic investigations are detailed within. Additionally, our efforts to develop an asymmetric variant of this reaction are enclosed.
\r\n\r\nChapter 4 discusses the development of a copper-catalyzed alkylation of N-heterocycles with \u03b1-halolactams in the absence of light. The scope of the reactivity is detailed within. Mechanistic studies contained in this section suggest a unique and interesting reaction pathway\u2014one that does not proceed through a radical intermediate.
\r\n\r\nChapter 5 presents a novel class of organosilane electrophiles employed in an enantioconvergent nickel-catalyzed cross-coupling reaction. Here, the development of the reaction, scope of reactivity, and initial mechanistic insights are discussed.
\r\n\r\n", "doi": "10.7907/G3Q9-8F81", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:10956", "collection": "thesis", "collection_id": "10956", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05282018-184138570", "type": "thesis", "title": "Copper Carbazolides in Photoinduced C\u2013N Couplings", "author": [ { "family_name": "Ahn", "given_name": "Jun Myun", "orcid": "0000-0002-8181-908X", "clpid": "Ahn-Jun-Myun" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" } ], "thesis_committee": [ { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Photoinduced, copper-catalyzed reactions of organohalides have emerged in recent years as a powerful tool to construct a wide array of C\u2013N bonds, which are prevalent in organic materials and polymers, pharmaceuticals, natural products, and ligands in transition metal catalysts. Described herein is the study and applications of copper complexes ligated by carbazole and its derivatives in photoinduced, copper-catalyzed C\u2013N bond-constructing transformations. Various areas of synthetic inorganic and organic chemistry are explored, including in-depth mechanistic elucidation, ligand and catalyst design, reaction development, as well as spectroscopic and structural characterization of reactive copper complexes.\r\nChapter 2 describes the mechanistic investigation on photoinduced, copper-catalyzed couplings of carbazoles with unactivated alkyl halides. A wide array of mechanistic tools suggests the viability of an out-of-cage C(sp\u00b3)\u2013N coupling pathway. Spectroscopic and structural characterization data of the key intermediates are detailed.\r\nChapter 3 outlines the design and preparation of a new copper-based photoredox catalyst supported by a tridentate bis(phosphino)carbazole ligands. The ground- and excited-state properties of the new photocatalyst are examined.\r\nChapter 4 details the development of photoinduced, copper-catalyzed C(sp\u00b3)\u2013N couplings of carbamates with unactivated alkyl bromides using the new copper photoredox system. The scope with respect to the nucleophile and the electrophile and mechanistic investigations are communicated.\r\nChapter 5 illustrates the chemistry of copper complexes supported by bidentate (phosphino)carbazole ligands. A diverse array of copper complexes in both the S = 0 and S = 1/2 states are reported, including a rare, paramagnetic copper\u2013phosphine complex that may serve as a structural model for key copper intermediates of the enantioselective C(sp\u00b3)\u2013N couplings of carbazoles.", "doi": "10.7907/H8AP-G249", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:9596", "collection": "thesis", "collection_id": "9596", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03012016-104838419", "primary_object_url": { "basename": "Yufan Liang_Thesis_2016.pdf", "content": "final", "filesize": 23804153, "license": "other", "mime_type": "application/pdf", "url": "/9596/1/Yufan Liang_Thesis_2016.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Applications of Nickel-Catalyzed Cross-Coupling Methods in the Synthesis of Organofluorine Compounds", "author": [ { "family_name": "Liang", "given_name": "Yufan", "orcid": "0000-0002-0533-2982", "clpid": "Liang-Yufan" } ], "thesis_advisor": [ { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Fu", "given_name": "Gregory C.", "clpid": "Fu-G-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The applications of nickel-catalyzed cross-coupling strategy to the synthesis of organofluorine compounds are explored in this thesis.
\r\n\r\nChapter 2 describes the development of the first enantioselective cross-coupling method using secondary geminal dihalides as electrophiles. This method provides a unique approach for the generation of enantioenriched tertiary alkyl fluorides. These cross-coupling products can be further transformed into a variety of potentially valuable chiral building blocks.
\r\n\r\nChapter 3 describes the development of a practical and versatile Negishi alkylation method employing \u03b1-halo-\u03b1-perfluoroalkyl secondary electrophiles. Target molecules bearing perfluoroalkyl-substituted (including trifluoromethyl-substituted) tertiary carbons can be easily generated from fluorinated electrophiles. Competition experiments and mechanistic studies have been performed to reveal the unique properties of these electrophiles and also prove the existence of alkyl radicals.
\r\n\r\nChapter 4 describes the development of an asymmetric Negishi arylation protocol with \u03b1-halo-\u03b1-trifluoromethyl secondary electrophiles. This study provides a unique approach to construct trifluoromethyl-substituted tertiary stereocenters. The optimized condition can also be directly applied to substrates bearing an array of fluoroalkyl groups.
\r\n\r\nChapter 5 details the progress towards the development of an asymmetric alkynylation method employing \u03b1-halo-\u03b1-trifluoromethyl secondary electrophiles. Preliminary studies also demonstrate that the protocol we developed has the potential to be used for other non-fluorinated secondary electrophiles.
\r\n", "doi": "10.7907/Z9CF9N45", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" } ]