This thesis examines the effects of coordinating highly sterically demanding and strongly electron donating saturated N-heterocyclic carbenes (NHCs) at late transition metal centres. Chapter III details the synthesis of a range of iridium complexes of the type (NHC)2IrHxCly [x = 1, 2; y = 0, 1], bearing the saturated NHCs 5-Mes, 6-Mes and 7-Mes. Unusually facile activation chemistry is observed in the reaction of [Ir(COE)2Cl]2 with 6-Mes and 7-Mes to form the doubly cyclometallated species (6-Mes')2IrH and (7-Mes')2IrH, which were fully characterised. The responses of these complexes to the addition of dihydrogen and HCl were studied, leading to the controlled synthesis of range of precursors to 14-electron iridium cations. In Chapter IV the formation of low valent iridium cations with weakly coordinating anions is targeted. Isolation of the cationic complexes [(NHC)(NHC')IrH][BArf4] and [(NHC)2IrH2][BArf4] (NHC = 6-Mes, 7-Mes) showcases the stabilising power offered by these expanded ring systems. This allowed the study the interaction of these low valent species with a range of amine-borane substrates which are known to be readily dehydrogenated. Thermodynamic data on the C-H bond activation processes occurring at these iridium centres were able to be obtained due to facile, reversible oxidative addition of C-H bonds across the 14-electron iridium. Chapter V focuses on the effects of increasing the steric bulk of these NHCs to limit the coordination of multiple ligands at the metal centre. Use of 2,6-diisopropyl-phenyl (Dipp) groups on the expanded ring NHCs, instead of mesityl groups, leads to an unprecedented mode of reactivity with [Ir(COE)2Cl]2. Activation and cleavage of C-N bonds in the carbene ring is observed, resulting in an open chain ligand chelating to the metal centre. Activation of the backbone in this manner has allowed the synthesis of saturated NHCs bearing a weakly coordinating anion on the ring. Here the first example of an anionic, saturated NHC is reported. In Chapter VI these highly sterically demanding NHCs are exploited to stabilise active species in low valent gold chemistry. The extreme steric bulk of the 6-Dipp ligand disfavours reduction of Au(I) to Au(0), however the resulting cation is observed to interact strongly with the weakly coordinating anion, [BArf4]-. Thus, attempts were made to optimise the anion and conditions to isolate a catalytically relevant intermediate. The strong donating power of these expanded ring NHCs is also exploited to activate gold hydride complexes of the type (NHC)AuH (NHC = 6-Dipp, 7-Dipp). Analogues of [H3]+ containing gold atoms ([{LAu}2H]+ and [LAuH2]+) supported by expanded ring NHCs were also targeted.

The ever increasing demand for more efficient and environmentally benign routes for synthesizing target compounds, has led to the use of organometallic catalysts. This demand has created the need to understand the mechanistic details that are at work in these organometallic catalytic cycles. Along with this, there is a demand for new organometallic catalysts that are tailored for specific transformations. This presents a myriad of challenges for organometallic chemists. Unfortunately, it is often difficult to gain an understanding of the reaction mechanisms at work when the intermediates are too short lived to be observed in the condensed phase. It is also very time consuming to synthesize, purify, and characterize organometallic catalysts following standard condensed phase methods. Therefore, it would be beneficial to probe organometallic reactions in a way that the inherent reactivity of the organometallic complex can be uncovered and where purity is not a prerequisite. Using an ion-trap mass spectrometer that has been modified to allow introduction of neutral reagents to the buffer gas, organometallic ion-molecule reactions can be probed in an environment free from solvation effects. This enables the study of the inherent reactivity of the complexes and also provides insight into reaction mechanisms by allowing reactive intermediates to be probed. In addition, organometallic complexes probed in this manner do not need to be pure due to ability of the ion trap to function as a mass filter. This results in a quick and efficient method. This dissertation presents results found during the investigation of the reactions and mechanistic details of gold, silver, and iridium complexes using a modified ion-trap mass spectrometer.

Les réactions de couplage métallocatalysées mises en avant par l'attribution du Prix Nobel de Chimie 2010 permettent la création de liaison C-C impossible par les réactions de type SN1 ou SN2. Or, les composés auxquels elles donnent accès sont très utilisés dans le domaine pharmaceutique, agrochimique ou encore dans celui de la chimie supramoléculaire. Si les réactions sont efficaces, les agents de couplages sont souvent peu accessibles et/ou peu éco(nomique/logique)-compatibles. Les triarylbismuthines lèvent en partie ces limitations, car tous les atomes de ces organométalliques participent aux processus et ces composés sont considérés comme non toxiques mais les réactions engageant ce type d'organométalliques souffrent de leur dimérisation. Afin de lever cette limitation, nous avons développé un système catalytique plus " vert" utilisant le PEPPSI comme pré-catalyseur sur une réaction test. Ces nouvelles conditions donnent généralement d'excellents rendements en série biarylique comme hétérobiarylique. La gamme des substituants sur le dérivé halogéné est très étendue mais plus limitée sur la bismuthine. Ce système catalytique a ensuite été utilisé sans modification dans les réactions domino d'élimination/couplage. Une étude cinétique comparative par GC/MS et RMN 13C a permis de montrer qu'une élimination d'ordre 2 avait lieu avant le couplage. De plus il y a un effet coopératif entre les ions fluorures et la bismuthine : celle-ci joue donc un double rôle : agent organométallique doux de couplage et base. L'ambiguïté mécanistique ainsi levée, il a été permis d'envisager une chimiosélectivité en fonction des divers états d'hybridation du carbone portant le brome au moment du couplage. Plusieurs méthodes d'accès à des molécules de structures Ar-Ar-C C-Ar à géométries variables peuvent être obtenues rapidement. Le système catalytique a également permet l'activation de liaison C-Br de bromocoumarines. Ainsi, il est possible de réaliser le couplage sur les positions 3-, 4- et 6-. L'ordre de réactivité a été déterminé ce qui a permis de réaliser des monocouplages parfaitement sélectifs sur les 3,4- ou 3,6- dibromocoumarines, dont les applications biologiques suscitent un grand intérêt. Le nouveau système catalytique a donc éliminé le problème de dimérisation des triarylbismuthines et donne potentiellement accès à des molécules intéressantes pour leurs propriétés physiques ou biologiques / Metallocatalysed crosscoupling reactions have been highlighted by the attribution of the 2010 Nobel Chemistry Price since they allow CC bond formation when classical SN1 or SN2 do not permit it. Furthermore, they give access to many pharmaceutics and agronomic compounds but also molecules used for their supramolecular properties. Nowadays, reactions are really efficient but reactants are not always readily accessible and can't be classified as green reagents. Since all its atoms act over the catalytic process and because they are not considered as toxic so far, triarylbismuthines may be a good alternative to circumvent the limitation described above. However, they suffer a main drawback, their reductive dimerisation. In order to avoid this side-reaction, a new greenest process has been developed on a benchmark reaction based on PEPPSI, an NHC/Pd catalyst. These conditions gave usually excellent yields, either for the biaryle or heterobiaryle crosscoupling reaction. The range of substituents is really wide on the aryle halide moiety but slightly more limited on the triarylbismuthine reagents. Then, this catalytic process has been applied without modification to an elimination/crosscoupling domino reaction. A GC/MS and 13C NMR supported comparative kinetic study showed that a 2nd order elimination take place before the C-C bond formation. Fluoride anion and triarylbismuthine act together. Therefore triarylbismuthine play a dual role: base and aryl transfer reagent. This mechanism study led to chimioselective reactions that allow many paths for the synthesis of Ar-Ar-C C-Ar containing compounds with a good control on geometry of this highly conjugated structure. This catalytic process allows also bromocoumarine C-Br bond activation. Thus, crosscoupling may be selectively performed at the 3-, 4- or 6- position of coumarines. The reactivity order difference of these positions even allow hightly selective mono crosscoupling reaction on 3,4- or 3,6-dibromocoumarines for further biological application. To conclude, our PEPPSI based greenest process avoid the dimerisation of bismuthines and give easy access to many compounds of great interest either for their biological or physical properties

Carbonyl complexes of Ni(0) incorporating two N-heterocyclic carbenes of the type Ni(CO)2(NHC)2 (NHC = ICy [N, N'-bis(cyclohexylimidazol)-2-ylidene], IMes [N, N'- bis(2, 4, 6-trimethylphenyl)-imidazol)-2-ylidene]) have been prepared. The complexes Ni(CO)2(ICy)2 (8) and Ni(CO)2(IMes)2 (9) have been synthesized and characterized by single crystal X-ray diffraction. The enthalpy of substitution reactions of Ni(CO)2(NHC) (NHC = ItBu [N, N'-bis(tert-butylimidazol)-2-ylidene], IAd [N, N'-bis(1- adamentylimidazol)-2-ylidene]) with NHC and tertiary phosphine ligands leading to the formation of Ni(CO)2(L)2 (L = NHC, PR3) complexes have been determined. The solution calorimetric investigations reiterate the greater electron donating property of the NHC ligands compared to tertiary phosphines. Thermochemical studies of the substitution reactions of Ni(CO)2(NHC) (NHC = ItBu, IAd) forming complexes (8) and (9) led to the determination of average bond dissociation energy of Ni-NHC (NHC = ICy, IMes) and Ni-P (P = PCy3, PPh3, P(p-Tol)3, P(m-Tol)3).

Die vorliegende Arbeit befasst sich mit Untersuchungen von Element-Element- Bindungsaktivierungsreaktionen des dinuklearen Nickel(0)-NHC-Komplex [Ni2(iPr2Im)4(COD)] A mit verschiedenen reaktionsträgen Substraten, die ihrerseits wichtige Ausgangsstoffe für katalytische Anwendungen sind. Die Arbeit gliedert sich dabei in vier verschiedene Teile. / The present work is concerned with investigations of element-element bond activation reactions of the dinuclear NHC-ligated nickel(0)-complex [Ni2(iPr2Im)4(COD)] A with inert substrates, which are themselves important compounds for catalytic transformations. This work is divided into four parts.

Thesis advisor: Amir H. Hoveyda / Chapter 1. We have developed a single-vessel catalytic protocol for double protoboryl additions to terminal alkynes with B2(pin)2 promoted by Cu complex derived from chiral N-heterocyclic carbene (NHC), to achieve enantiomerically enriched versatile vicinal diborons. Since an alkenyl(pinacolato)boron, which was in situ generated by the first protoboration of a terminal alkyne, can serve as an effective substrate for the second protoboration (alkenylboron can allow delocalization of π electrons of olefin to a partially vacant p orbital on boron), single-vessel catalytic process with 2 equiv. of B2(pin)2 in the presence of sulfonate-bearing chiral NHC–Cu complex, affords enantiomerically enriched 1,2-diborons in up to 93% yield and 97.5:2.5 enantiomeric ratio (e.r.). Site-selective Pd-catalyzed cross-coupling with alkenyl bromide shows the versatility of the resulting diboron compounds, which delivers the coupling product efficiently. Interestingly, only the less hindered, primary C–B bond on vicinal diboron compound participates in the cross coupling. Chapter 2. Cu-catalyzed protocol for selective formation of α-alkenylborons has been demonstrated. With achiral NHC–Cu complex, readily prepared from commercially available imidazolinium salt, various terminal alkynes are converted to internal alkenylborons in up to 93% yield with high to exclusive α selectivity. Propargyl ethers, amides and aryl alkynes are proved to be suitable substrates. Utility of α-alkenylborons is demonstrated by conversion to methyl ketone and synthesis of cyclic alkenylboron compound. In addition, when Cu complex bearing a stronger electron-donating NHC is used, the site selectivity of protoboration reaction becomes reversed, which delivers the alternative isomer, β-alkenylboron efficiently. By altering the steric and electronic nature of NHC, site selectivity is dramatically changed. Mechanistic basis for site selectivity is presented. Chapter 3. Efficient and selective protocol for synthesis of enantiomerically enriched silylborons is described. In the presence of achiral NHC–Cu complex, site- and stereoselective protosilyl additions to terminal alkynes afford a wide range of alkyl- and aryl-substituted (E)-β-alkenylsilanes. Chiral monodentate NHC−Cu complex promotes enantioselective protoboration of alkyl- or alkenyl-bearing alkenylsilanes, delivering vicinal borosilanes with up to 96.5:3.5 e.r. When an alkene bearing both silyl and aryl groups is utilized, on the other hand, geminal silylboron is obtained with high enantio- (93:7–98.5:1.5 e.r.) and site selectivity (up to >98% geminal). In this case, we have reasoned that the electronic attribute of aryl unit is more dominant than the silyl group to control site selectivity. To demonstrate the utility of the Cu-catalyzed transformation, we have illustrated the formal synthesis of bruguierol A, natural product active against Gram-positive and also Gram-negative bacteria. The key intermediate geminal borosilane is provided by sequential NHC–Cu-catalyzed protosilylation and protoboration of terminal alkyne in 77% overall yield with 97.5:2.5 e.r. and 97% site selectivity. Additionally, stereochemical models to account for levels and trends in site- and enantioselectivity are proposed. Chapter 4. New methods for enantioselective protonation of 2-B(pin)-bearing allylcopper, which is in situ generated by site-selective Cu–B addition to 1,1-disubstituted allene, are presented. Transformations are promoted by a chiral NHC–Cu complex, affording an alkenylboron containing α-carbon stereogenic center. Enantiomerically enriched aryl-, heteroaryl- and silyl-bearing alkenylborons are generated in high yield (up to 98%) and selectivities (up to >98% site selectivity and 96.5:3.5 e.r.). To explore the utility of enantiomerically enriched alkenylborons, we have developed Cu-catalyzed enantioselective allylic alkenyl addition to allylic phosphate. A chiral NHC–Cu complex promotes the allylic substitution of enantiomerically enriched alkenylboronic acid with ally phosphate to deliver 1,4-diene in 62% yield with 96:4 d.r. (>98% stereoselectivity). Chapter 5. We have developed a single-vessel, multicomponent process to synthesize N-bearing quaternary carbon stereogenic centers with exceptional diastereo- (>98:2 d.r. for all cases) and high enantioselectivity (88:12 to >99:1 e.r. except one case). Especially, protecting group-free ketoimine (“N–H” ketoimine), which can be prepared by alkylation of a readily available nitrile, has been utilized for the study. The transformation of “N–H” ketoimine is very useful because the obtained amine has no protecting group, which allows us to avoid the deprotection step as well as to be able to choose appropriate protecting group for subsequent chemical reactions. By oxidation of α-tertiary carbamine with NaBO3, β-amino ketones (Mannich reaction product) are obtained in up to 83% yield. A stereochemical model to account for the level of diastereo- and enantioselectivity are presented using DFT calculations. To show the utility of the present method, we have synthesized a medicinally active compound, which was studied for Alzheimer’s disease. The Cu-catalyzed protocol delivers the core structure of the target molecule with exclusive diastereo- and enantioselectivity (>98:2 d.r. and 99.5:0.5 e.r.). / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Catalytic enantioselective reactions are of great importance in synthetic organic chemistry. Thus, development of efficient, selective and easily accessible catalyst for various bond formations is the main task in our laboratories. First, we have developed the first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls, promoted by a chiral Lewis basic N-heterocyclic carbene. The valuable β-boryl carbonyls were further used in complex molecule syntheses. The mechanism of these C–B bond formations was studied in details. We have also developed a practical method for enantioselective addition of an allene unit to aryl-, heteroaryl- and alkyl-substituted Boc-aldimines. These efficient C–C bond formations, catalyzed by an aminophenol-derived boron-based catalyst, were further utilized in succinct syntheses of anisomycin and epi-cytoxazone. Finally, chiral NHC–Cu complexes were employed for site-, diastereo- and enantioselective silyl conjugate additions to acyclic and cyclic dienones and dienoates. The precious enantiomerically enriched allylsilane obtained can be converted into a ketone-aldol type product, which is difficult to access through alternative methods. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir Hoveyda / Chapter 1: A review of recent iron catalyzed cross coupling advances. Abstract: Herein, advances in iron catalyzed cross coupling from 2010-2015 are thoroughly reviewed. Newly developed protocols and the mechanistic work that has been conducted to gain understanding of these systems are discussed. Specific emphasis is placed on the techniques used for mechanistic investigations. Chapter 2: Cross coupling applications of pyridyl(diimine) iron complexes. Abstract: Versatile and redox noninnocent pyridyl(diimine) iron complexes were explored for catalytic ability in iron catalyzed cross coupling reactions. These complexes were found active for the coupling of benzyl halides and aryl Grignard reagents, producing moderate yields. Although active for the coupling of cyclohexyl chloride and aryl Grignard reagents, the catalytic ability of these complexes was not general for alkyl halides, and the majority of substrates readily underwent β- hydride elimination. Mechanistic studies indicated the role of PDIFe(I)Ph and PDIFe(0)(N2)2 as offcycle species. Additionally, these complexes were employed for the Suzuki-type coupling of alkyl halides with 1,1-bis(boronates), leading to the conclusion that the processes were instead base catalyzed. Chapter 3: Electronic structure analysis and catalytic applications of carbeno(diamidine) iron complexes. Abstract: Iron(II) pincer complexes carbeno(diamidine) iron dibromide [(CDA)FeBr2] and bis(N-heterocyclic carbene)pyridine iron dibromide [(CNC)FeBr2] were examined by magnetic circular dichroism and density functional theory studies to invesitgate the effect that NHC moieties have on electronic structure and bonding in tridentate pincer ligands. The increased Fe-C bonding and pincer-donating abilities that result from NHC incorporation have a direct impact on spin state and observed ligand fields. Additionally, the position of the NHC moiety on the tridentate ligand and the overall geometry of the molecule were found to effect the net donor ability of the pincers and the strength of the iron-pincer interactions. Three new variations of the CDA ligand were developed and evaluated for catalytic ability in olefin hydrogenation and atom transfer radical polymerization reactions. While iron CDA complexes were found to be mediocre catalysts for both transformations, a cobalt CDA dimer complex was developed that showed promising catalytic activity for olefin hydrogenation. Chapter 4: The direct functionalization of lactide. Abstract: In an effort to provide cyclic diesters that could generate useful and biodegradable polymers, the direct functionalization of lactide was pursued. Lactide undergoes ring opening under a wide range of conditions, and thus traditional methods used for the functionalization of lactones could not be employed here. Typical routes for the formation of cyclic diesters involve multi-step syntheses and low yielding cyclization reactions. Herein, C-H activation and soft enolization have been identified as promising avenues toward the direct functionalization of lactide. Palladium catalyzed C-H activation was not amenable for lactide, however, soft enolization techniques led to low yields of the desired functionalized product. / Thesis (MS) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. In this chapter, the ability of chiral bidentate N-heterocyclic carbenes (NHCs) to activate alkylmetal reagents directly in order to promote C&#8210;C bond forming reactions in the absence of a Cu salt is presented. Highly regio- and enantioselective Cu-free allylic alkylation reactions of di- and trisubstituted allylic substrates with organomagnesium, organozinc, and organoaluminum reagents are demonstrated. Chiral bidentate sulfonate-bearing NHC-Zn and NHC-Al complexes are isolated and fully characterized. Based on crystal structures of these catalytic complexes, mechanistic details regarding Cu-free allylic alkylations with alkylmetal reagents are proposed. Chapter 2. New methods for efficient and highly enantioselective Cu-catalyzed allylic alkylation reactions of a variety of trisubstituted allylic substrates with alkylmagnesium and alkyl-, aryl-, 2-furyl-, and 2-thiophenylaluminum reagents are presented. Transformations are promoted by a chiral NHC complex in the presence of commercially available, inexpensive and air stable CuCl2*H2O. Enantiomerically enriched compounds containing difficult-to-access all-carbon quaternary stereogenic centers are obtained. Chapter 3. New methods for highly site- and enantioselective Cu-catalyzed allylic alkylation reactions of allylic phosphates with vinylaluminum reagents are presented. The requisite vinylaluminums are prepared by reaction of readily accessible terminal alkynes with DIBAL-H and used directly without further purification. Vinyl additions are promoted in the presence of a chiral bidentate sulfonate-based NHC complex and a Cu salt. The desired SN2' products are obtained in >98% E selectivities, >98% SN2' selectivities, >98% group selectivities (<2% i-Bu addition) and high enantioselectivities. The enantioselective total synthesis of the natural product bakuchiol highlights the versatility of the one-pot hydroalumination/Cu-catalyzed enantioselective allylic vinylation process. Chapter 4. Efficient and highly site-selective Cu-catalyzed hydroboration reactions of 1,2-disubstituted aryl olefins with bis(pinacolato)diboron (B2(pin)2) are presented. Transformations are promoted by an NHC-Cu complex in the presence of MeOH, affording only secondary &#946;-boronate isomers. A Cu-catalyzed method for the synthesis of enantiomerically enriched secondary alkylboronates promoted by chiral NHC complexes is disclosed. Chapter 5. A new method for efficient and site-selective tandem Cu-catalyzed copper-boron additions to terminal alkynes with B2(pin)2 in the presence of an NHC-Cu complex is demonstrated. In a one-pot process, Cu-catalyzed hydroboration of alkynes provides vinylboronates in situ, which undergo a second site-selective hydroboration to afford vicinal diboronates. Highly Enantiomerically enriched diboronates obtained through Cu-catalyzed enantioselective dihydroboration in the presence of chiral bidentate sulfonate-based NHC-Cu complex are obtained. The control of site selectivity in the first-stage hydroboration of alkynes is critical for efficient and highly enantioselective reactions in the tandem dihydroboration. Functionalizations of the vicinal diboronates described herein underline the significance of the current method. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Die vorliegende Arbeit befasst sich zum einen mit der Synthese und Reaktivität des zweiwertigen Nickel-Biscarben-Komplexes trans-[Ni(iPr2Im)2Br2], zum anderen mit der Aktivierung von C–F-Bindungen fluorierter Aromaten und dem Einsatz von [Ni2(iPr2Im)4(COD)] in der stöchiometrischen und katalytischen Hydrodefluorierung. / The present work deals with the synthesis and reactivity of the divalent nickel biscarbene compound trans-[Ni(iPr2Im)2Br2] on the one hand and the activation of C–F bonds of fluorinated aromatics and the use of the zerovalent complex [Ni2(iPr2Im)4(COD)] in stoichiometric and catalytic hydrodefluorination reactions on the other.