Thesis advisor: Masayuki Wasa / Thesis advisor: Amir H. Hoveyda / This dissertation describes the development of cooperative catalyst systems for the regio- and enantio-selective α- and β-amino C-H functionalization of N-alkylamines, inspired by the concepts of frustrated Lewis pairs (FLPs). Prior to this dissertation research, the development of effective and broadly applicable catalytic protocol to transform amino C-H bonds with high enantioselectivity remained as a formidable problem. In Chapter 1, the recent advances in the field of amino C-H functionalization through hydride transfer process that served as intellectual foundations for this dissertation research is presented. As highlighted in the first chapter, key challenges of amino C-H functionalization are: (1) unreactive nature of α, β- and/or γ-amino C-H bonds, (2) requirement for the use of precious metal-based catalysts and external oxidants under acidic/basic and harsh conditions, (3) use of directing groups for regioselectivity, and (4) poor functional group tolerance. Inspired by the unique capability of FLPs to activate otherwise unreactive molecules while disfavoring undesirable acid-base complexation, we have developed a protocol for enantioselective α-amino C-H functionalization of N-alkylamines, where chiral and achiral Lewis acid catalysts work cooperatively (Chapter 2). The application of the cooperative catalyst system comprising of B(C6F5)3, a chiral Lewis acid, and a Brønsted base to the enantioselective β-amino C-H functionalization is described in Chapter 3. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Masayuki Wasa / Thesis advisor: Amir H. Hoveyda / This dissertation describes the development of cooperative catalyst systems that contain an achiral Lewis acid and a chiral Lewis acid that may have overlapping functions but play their independent roles to promote enantioselective C–C bond formations. Chapter 1 provides a summary of recent advances made in the field of enantioselective cooperative catalysis that served as intellectual foundations for this dissertation research. As it will be discussed in the first chapter, key limitations of cooperative catalysis are: (1) undesirable catalyst deactivation which occurs due to acid/base complexation, (2) requirement for base sensitive pronucleophiles and acid sensitive electrophiles, and (3) poor reaction efficiency. In an effort to overcome these fundamental limitations, we have developed “frustrated” Lewis pair (FLP)-based catalyst systems that consist of potent and sterically encumbered Lewis acids used in pair with bulky N-containing Lewis bases. To demonstrate the potential of the novel FLP catalyst system, we describe our work involving the enantioselective Conia-ene-type cyclization (Chapter 2). In the subsequent chapter (Chapter 3), we discuss the application of the FLP catalysts for enantioselective β-amino C–H functionalization reactions. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Computational chemistry is a branch of modern chemistry that utilizes the computers to solve chemical problems. The fundamental of computational chemistry is Schrödinger equation. To solve the equation, researchers developed many methods based on BornOppenheimer Approximation, such as Hartree-Fock method and DFT method, etc. Computational chemistry is now widely used on reaction mechanism study and new chemical designing. In the first project described in Chapter 3, we designed phosphine oxide modified Ag3, Au3 and Cu3 nanocluster catalysts with DFT method. We found that these catalysts were able to catalyze the activation of H2 by cleaving the H-H bond asymmetrically. The activated catalyst-2H complex can be further used as reducing agent to hydrogenate CO molecule to afford HCHO. The mechanism study of these catalysts showed that the electron transfer from electron-rich metal clusters to O atom on the phosphine oxide ligand is the major driving force for H2 activation. In addition, different substituent groups on phosphine oxide ligand were tested. Both H affinity of metal and the substituent groups on ligand can both affect the activation energy. Another project described in Chapter 4 is the modelling of catalyst with DFT. We chose borane/NHC frustrated Lewis pair (FLP) catalyzed methane activation reaction as example to establish a relationship between activation energy and catalysts’ physical properties. After performing simulation, we further proved the well-accepted theory that the electron transfer is the main driving force of catalysis. Furthermore, we were able to establish a linear relationship for each borane between activation energy and the geometrical mean value of HOMO/LUMO energy gap (ΔEMO). Based on that, we introduced the formation energy of borane/NHC complex (ΔEF) and successfully established a generalized relationship between Ea and geometrical mean value of ΔEMO and ΔEF. This model can be used to predict reactivity of catalysts.

Mechanisms of reactions of the frustrated Lewis pairs (FLPs) with carbon dioxide (CO2) and hydrogen (H2) are studied by using quantum chemical modelling. FLPs are relatively novel chemical systems in which steric effects prevent a Lewis base (LB) from donating its electron pair to a Lewis acid (LA). From the main group of the periodic table, a variety of the electron pair donors and acceptors can create an FLP and the scope of the FLP chemistry is rapidly expanding at present. Representative intermolecular FLPs are phosphines and boranes with bulky electron-donating groups on phosphorus and bulky electron-withdrawing groups on boron – e.g., the tBu3P/B(C6F5)3 pair. The intramolecular FLPs feature linked LB and LA centers in one molecule. Investigations of the FLP reaction mechanisms were carried out using the transition state (TS) and the potential energy surface (PES) calculations plus the Born-Oppenheimer molecular dynamics (BOMD) as an efficient and robust implementation of general ab initio molecular dynamics scheme. In BOMD simulations, quantum and classical mechanics are combined. The electronic structure calculations are fully quantum via the density functional theory (DFT). Molecular motion at finite (non-zero) temperature is explicitly accounted for at non-quantized level via Newton’s equations. Due to recent advancements of computers and algorithms, one can treat fairly large macromolecular systems with BOMD and even include significant portion of the first solvation shell surrounding a large reacting complex in the molecular model. Main results are as follows. It is shown that dynamics is significant for understanding of FLP chemistry. The multiscale nature of motion – i.e., light molecules such as CO2 or H2 versus a pair of heavy LB and LA molecules – affects the evolution of interactions in the reacting complex. Motion which is perpendicular to the reaction coordinate was found to play a role in the transit of the activated complex through the TS-region. Regarding the heterolytic cleavage of H2 by tBu3P/B(C6F5)3 FLP simulated in gas phase and with explicit solvent, it was found that (i) the reaction path includes shallow quasi-minima “imbedded” in the TS-region, and (ii) tBu3P/B(C6F5)3 are almost stationary while proton- and hydride-like fragments of H2 move toward phosphorous and boron respectively. For binding of CO2 by tBu3P/B(C6F5)3 FLP, it was found that (i) the reacting complex can “wander” along the “potential energy wall” that temporarily blocks the path to the product, and (ii) the mechanism can combine the concerted and two-step reaction paths in solution. The discovered two-step binding of CO2 by tBu3P/B(C6F5)3 FLP involves solvent-stabilized phosphorus-carbon interactions (dative bonding). These and other presented results are corroborated and explained using TS and PES calculations. With computations of observable characteristics of reactions, it is pointed out how it could be possible to attain experimental proof of the results. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 6: Accepted.</p><p> </p>

Le concept de “paires frustrées de Lewis” (plus communément désignés par l’acronyme anglais FLPs) a suscité un vif intérêt depuis sa formulation en 2006. Initialement décrit à partir d’une phosphine encombrée comme base de Lewis et d’un borane comme acide de Lewis pour l’activation coopérative d’hydrogène sans métal, ce concept a été ensuite très largement développé en utilisant divers éléments du groupe principal (N/B, P/Al, N/Al …). Le concept a ensuite été étendu aux métaux de transitions pour pallier cette faiblesse: sont ainsi apparues les premières paires frustrées de Lewis organométalliques (OmFLPs). Dans le but de développer de telles OmFLPs, nous nous sommes intéressés à la synthèse de complexes cationiques titanocèniques et zirconocèniques en présence d’une amine. La première partie de cette thèse présente les travaux précédemment décrits sur les ligands azotés, en vue de synthétiser des complexes du groupe 4 N-fonctionnalisés. Une description plus détaillée du concept de FLP est ensuite réalisée, et un parallèle est fait avec des concepts connexes (coopérativité métal-ligand, systèmes ambiphiles). La seconde partie de ce manuscrit développe la synthèse de nouveaux ligands (aminomethyl)cyclopentadiènylure de potassium ainsi qu’une étude de leur coordination aux métaux du groupe 4. Cette étude a permis d’accéder à toute une série de nouveaux complexes dichlorotitanocènes et zirconocènes porteurs d’une fonction amine tertiaire encombrée (diisopropylaminyl et 2,2,6,6-tétraméthylpipéridine) à proximité du centre métallique. Ces travaux ont montré que l’amine ne se coordine pas audit centre métallique. Les métallocènes ainsi formés ont ensuite été transformés en cation afin de renforcer le caractère acidité de Lewis du centre métallique. Ces espèces ont montré une réactivité inattendue donnant lieu à des réarrangements par activation CH au voisinage de l’atome d’azote. Ces réarrangements ainsi que des études mécanistiques font l’objet du troisième chapitre. La quatrième partie de ce mémoire porte sur la synthèse de complexes phosphido- et amidotitanocènes cationiques. Ces complexes montrent une très bonne activité en catalyse d’hydrogénation de petites molécules dans des conditions relativement douces, vraisemblablement pour des raisons d’effets coopératifs entre le métal et le ligand. Dans une dernière partie, la synthèse de complexes titanocéniques cationiques portant une fonction iminophosphorane est développée, suivie d’une étude de réactivité de ces complexes en tant que paires frustrées de Lewis organométalliques. / In 2006, the concept of “frustrated Lewis pairs” (called FLPs) was introduced. The main characteristic of these compounds is their ability to activate cooperatively small molecules without the use of a metal (H2, CO2, alkene alkyne…). Initially based on P/B combination, the concept has been extended to several other main group elements (N/B, P/Al, N/Al …). Recently, FLPs have been extended to the transition metal realm. These organometallic FLPs (OmFLPs) are obviously non-metal free systems but they extend significantly the scope of FLP applications. Seeking to develop such systems, a research toward new omFLP combinations (N/Ti+, N/Zr+) has been initiated in our group, based on the synthesis of N-based titanocene and zirconocene complexes. The first part of this manuscript deals with a survey of the literature of such compounds, and a more detailed presentation of FLPs and related concepts (metal-ligand cooperativity, ambiphilic ligands) are also developed. In a second chapter, the synthesis of new N-based cyclopentadienyl ligands and their coordination to group 4 metals is presented. The formation of a cationic complex is then developed in a third part on selected titanocenes. In these complexes, the amine function undergoes CH activation by the cationic metal centre, leading to unexpected rearrangements. Investigations on their plausible mechanism are also presented. In a fourth part, the synthesis of new cationic phosphido- and amidotitanocenes, discovered in the course of our study on OmFLPs, is developed. The cationic amidotitanocenes are shown to be catalytically active towards hydrogenation of small molecules. Lastly, the potential of cationic titanocenyl iminophosphoranes as OmFLPs, was developed.

La plateforme ferrocène est fréquemment utilisée en chimie de coordination et en catalyse pour son excellente résistance aux conditions de réaction poussées. Le squelette ferrocène permet de maîtriser l’agencement de plusieurs groupes fonctionnels d’intérêt. Des ansa-ferrocènes et des ferrocènes à conformation contrainte, permettant par leur structure de contrôler une proximité des groupes fonctionnels, ont été décrits.La première partie de cette thèse traite de la synthèse de cyclopentadiényles borylés disubstitués et de leur réaction d’assemblage pour la formation de métallocènes borylés à conformation contrainte. Des analyses par RMN et des calculs par DFT ont permis de mettre en évidence la diastéréosélectivité inédite de la synthèse.À partir de cette approche, la deuxième partie traite de l’agencement de fonctions acides/bases de Lewis sur une plateforme ferrocénique à conformation contrainte. La synthèse de cyclopentadiényles (P/B) trisubstitués a été initiée. La synthèse de ligands ambiphiles (P/B) par assemblage de cyclopentadiénures et l’influence des tertio-butyles sur leur conformation ont été explorées. Une nouvelle forme de couplage de spin à trois centres sans liaison covalente, impliquant la lacune du bore dans la transmission de spin 31P31P, a été observée en RMN pour un P,P,B-ferrocène très original.La troisième partie traite de la synthèse de ferrocènes (P/B) et (N/B) à conformation contrainte. La voie de synthèse alternative et diastéréosélective proposée s’est révélée efficace alors que le rôle des tertio butyles dans le contrôle conformationnel a été démontré. L’étude de leur réactivité de type paire frustrée de Lewis a été initiée avec le CO2. / Ferrocene platforms are useful in coordination chemistry and catalysis thanks to their robustness and versatile functionalization. Ferrocene backbone allows the implantation of several key functional groups in a restricted space, inducing close proximity and potential polyfunctional cooperation (see for instance ferrocenyl polyphosphine chemistry). Ansa ferrocene and ferrocene bearing conformational control inducing groups maximizing the proximity of key groups have been widely reported.The first part of this thesis focuses on the synthesis of new borylated cyclopentadienyl, and their use in formation of borylated metallocenes bearing conformational constraints. NMR analysis and DFT calculation exhibits the diastereoselectivity of assembly reaction.The second part deals with the arrangement of several Lewis acids and bases on a constraint ferrocene platform. Synthesis of trisubstituted cyclopentadienyl (P/B) has been initiated. Synthesis of ambiphilic ligands (P/B) by assembly reaction of cyclopentadienides and the influence of tert-butyl groups on their conformation have been explored. A new 31P31P spin coupling transmitted “through-space (nonbonded spin-spin coupling transmission) involving for the first time an empty orbital has been observed.The third part describes the synthesis of heteroannular (P/B) and (N/B) ferrocene directly from ferrocene functionalization. An efficient and diastereoselective synthesis has been developed and the influence of tert-butyl groups on the conformational control has been highlighted in both solid and solution state. Studies of the frustrated Lewis pair reactivity of these new ambiphilic ligands have been initiated by addition of CO2.