Palladium-catalyzed reactions of unactivated alkyl electrophiles

I. Palladium-Catalyzed Reactions of Unactivated Alkyl Electrophiles An overview of palladium-catalyzed reactions with sp3-hybridized electrophiles is presented. Cross-coupling reactions and carbonylations with alkyl halides and sulfonates are discussed in detail. II. Carbonylative Alkyl-Heck Type Cyclization of Alkyl Iodides A palladium-catalyzed carbonylative Heck-type cyclization of alkyl halides is described. Treatment of a range of primary and secondary alkyl iodides with catalytic palladium(0) under CO pressure forms a variety of synthetically versatile enone products. The reactivity described represents a rare example of a palladium-catalyzed Heck-type cyclization involving unactivated alkyl halides with β-hydrogens. Alkene substitution is well tolerated, and mono- and bicyclic carbocycles may be easily accessed. III. Alkyl-Heck Type Cyclizations of Alkyl Halides A palladium-catalyzed Heck-type reaction of unactivated alkyl iodides is described. This process displays broad substrate scope with respect to both alkene and alkyl iodide components and provides efficient access to a variety of cyclic products. The reaction is proposed to proceed via a hybrid organometallic-radical mechanism, facilitating the Heck-type process with alkyl halide coupling partners. IV. Palladium-Catalyzed Enantioselective Carbonylation of Alkyl Iodides A palladium-catalyzed enantioselective carbonylation of unactivated secondary alkyl iodides is reported. Preliminary results serve as proof-of-principle that hybrid radical-organometallic reactivity enables the stereoselective synthesis of α-chiral carbonyl compounds. V. Palladium-Catalyzed Ring Forming C-H Alkylations of Aromatic Systems A palladium-catalyzed intramolecular C-H alkylation of heteroarenes and arenes with unactivated alkyl halides is described. Preliminary results suggest this process is applicable to primary alkyl bromides and iodides and tolerates electron-rich and -poor aromatic systems. Our goal to be able to readily synthesize medium-ring fused aromatic structures so they can be readily applied to a variety of biologically active compounds.Doctor of Philosoph

Multicomponent Catalytic Reactions: Theoretical and Experimental Studies

193 p.In this thesis, Density Functional Theory (DFT) methods have been applied to study the mechanisms of three different multicomponent organic reactions. Also, a new synthetic procedure for the preparation of quinolinium salts is presented, and its mechanism also studied by DFT calculations. The thesis summarizes the work realized in two universities, and is divided in the following way: The first part of the thesis concerns the development of an experimentally simple, but mechanistically complex, reaction for the formation of quaternary quinolinium salts catalyzed by palladium salts. This multicomponent process uses readily available propylamine and its derivatives as starting materials. Through DFT studies a mechanism through the activation of two aliphatic C¿H bonds is proposed. The second part focuses on the mechanistic investigation of a three-components reaction, namely terminal alkynes, CO2 and allylic chlorides, mediated by an N-heterocyclic carbene catalyst that yields propargylic esters. By DFT calculations, the rate-limiting step was identified to be the reaction between the carboxylated catalyst and the allylic chloride. Through DFT, we were also able to understand the limitations of this reaction. The mechanism of a multicomponent reaction in which allylic alcohols are transformed into ¿-functionalized carbonyls was also investigated. The reaction relies on an umpolung strategy that enables to react enol intermediates with different nucleophiles. By DFT studies, a mechanism via enolonium intermediates is proposed, which provides an understanding of the selectivity of the reaction. The final chapter of the thesis deals with another multicomponent solvent-free reaction for synthesizing propargylamines catalyzed by manganese via a KA2 coupling. DFT studies were undertaken and a mechanism via manganese phenylacetylide species is proposed. 193 p

Computational Mechanistic Studies in Gold(I) Catalysis and Design of New Chiral Ligands

La recerca en catàlisi homogènia amb or ha proporcionat una eina única per la construcció l'eficient de molècules complexes mitjançant l'activació selectiva d'alquins. Malgrat això, la naturalesa dels intermedis de les reaccions de cicloisomerització catalitzades per or(I) continua sent desconcertant. Per tal d'entendre millor el mecanisme d'aquestes reaccions, s'han dut a terme estudis computacionals. S'ha investigat la naturalesa dels ciclopropil carbens d'or(I) i les seves possibles formes canòniques. Un estudi comparatiu dels mètodes DFT juntament amb la teoria QTAIM i l'anàlisi NBO van confirmar la presència de diferents intermedis en les cicloisomeritzacions d'enins. En aquest context, també es va calcular la formació selectiva de ciclopropans fusionats en trans mitjançant una reacció de ciclació en cascada, catalitzada per or(I). S'ha descobert un sistema catalític amb or que permet incorporar acetilè gas per formar sistemes complexes. La formació diastereoselectiva de bisciclopropà s'ha estudiat computacionalment. Malgrat l'èxit assolit per l'or(I) en catàlisi homogènia, les reaccions enantioselectives són encara escasses, particularment en el context de les reaccions intermoleculars. Per aquest motiu, es van preparar una sèrie de nous complexos d'or emprant fosfits quirals i es va assajar la seva activitat. També, es va desenvolupar la cicloadició enantioselectiva intermolecular d'alquins terminals i alquens utilitzant complexes dinuclears d'or(I) amb fosfines Josiphos. Els nostres estudis mecanístics indiquen que només un dels centres d'or(I) està directament implicat en l'activació de l'aquí, tot i que el segon és necessari per induir enantioselectivitat. Per tal de fer front a les limitacions de la catàlisi enantioselectiva, el nostre grup ha dissenyat una nova classe de catalitzadors d'or(I) que contenen pirrolidines 2,5-disubstituides C2 simètriques. Tal com revelen els NCI plots, el catalitzador exerceix l'estereocontrol mitjançant interaccions no covalents. A més, s'ha investigat la segona generació de lligands quirals a fi determinar el paper de cada component i predir enantioselectivitats més elevades.La investigación en catálisis homogénea con oro ha proporcionado una herramienta única para la construcción de moléculas complejas mediante la activación selectiva de alquinos. Sin embargo, la naturaleza de los intermedios de las reacciones de cicloisomerización catalizadas por oro(I) sigue siendo desconcertante. Para entender mejor el mecanismo de estas reacciones, se han llevado a cabo estudios computacionales. Se ha investigado la naturaleza de los ciclopropil carbenos de oro(I) y sus posibles formas canónicas. Un estudio comparativo de los métodos DFT junto con la teoría QTAIM y el análisis NBO confirmaron la presencia de diferentes intermedios en las cicloisomeritzaciones de eninos. En este contexto, también se calculó la formación selectiva de ciclopropanos fusionados en trans mediante una reacción de ciclación en cascada, catalizada por oro(I). Se ha descubierto un sistema catalítico con oro que permite incorporar acetileno gas para formar sistemas complejos. La formación diastereoselectiva de bisciclopropano se ha estudiado computacionalmente. A pesar del éxito alcanzado por el oro(I) en catálisis homogénea, las reacciones enantioselectivas son aún escasas, particularmente las intermoleculares. Por este motivo, se prepararon una serie de nuevos complejos de oro empleando fosfitos quirales y se ensayó su actividad. También, se desarrolló la cicloadición enantioselectiva intermolecular de alquinos y alquenos utilizando complejos dinucleares de oro(I) con fosfinas Josiphos. Nuestros estudios mecanísticos indican que sólo uno de los centros de oro está directamente implicado en la activación del aquino, aunque el segundo es necesario para inducir enantioselectividad. Para hacer frente a las limitaciones de la catálisis enantioselectiva, nuestro grupo ha diseñado una nueva clase de catalizadores de oro(I) que contienen pirrolidinas 2,5-disubstituidas. Tal como revelan los NCI plots, el catalizador ejerce la estereocontrol mediante interacciones no covalentes. Además, se ha investigado la segunda generación de ligandos quirales a fin determinar el papel de cada componente y predecir enantioselectividades más elevadas.Research in homogeneous gold catalysis has provided unique tool for the ready construction of molecular complexity through the selective activation of alkynes. However, the nature of intermediates in gold(I)-catalyzed cycloisomerization reactions was still puzzling. In order to shed light on the mechanism of these transformations, we performed computational studies. We investigated the nature of cyclopropyl gold(I) carbenes and their different canonical possible forms. Benchmark of DFT methods together with QTAIM theory and NBO analysis confirmed the presence of different intermediates in cycloisomerizations of enynes. In this context, we also computed the selective formation of trans-fused cyclopropanes by gold(I)-catalyzed cyclization cascade of functionalized dienynes. We discovered a Au(I)-catalyzed system for the incorporation of acetylene gas into complex frameworks. Formation of only one diastereomer of biscyclopropanes when mixing trans-stilbene with acetylene, has been rationalized by means of DFT calculations. Despite the success of gold(I) in homogeneous catalysis, highly enantioselective reactions are still relatively scarce, particularly in the context of intermolecular transformations. We prepared a series of novel chiral phosphite gold(I) complexes and tested their activity. Moreover, we developed the enantioselective intermolecular gold(I)-catalyzed [2+2] cycloaddition of terminal alkynes and alkenes using non C2-chiral Josiphos digold(I) complexes as catalysts. Our mechanistic studies indicate that only one of the gold(I) centers is directly involved in the activation of the alkyne, although the second one is required to induce the enantioselectivity. To address the limitations on enantioselective catalysis, our group have designed a new class of gold(I) catalysts containing remote C2-symmetric 2,5-disubstituted pyrrolidines. As revealed by NCI Plots, we proposed that the catalyst exerts the stereocontrol by non-covalent interactions. In addition, 2nd generation of chiral ligands have been investigated in order to determine the role of each component and predict the higher enantioselectivities

Quantum/classical simulation of molecular excited state dynamics and spectroscopy

The ability of modern quantum chemistry to answer ever more complex questions rises steadily. In this thesis, a comprehensive exploration of molecular photochemistry using high-level electronic structure methods for quantum-classical dynamics is presented. The first chapter introduces theoretical methods for simulating photodynamical processes, focussing on the relaxation of molecules in explicit atomistic environments. These approaches include nuclear wavepacket dynamics embedded within classical molecular dynamics. The presented Ehrenfest and multi-configurational Ehrenfest approaches are applied to small molecules surrounded by noble gas atoms. Furthermore, trajectory surface hopping is discussed, as, in later chapters, the program SHARC is used to perform such simulations. During this thesis, adaptive time-stepping and two new interfaces to electronic structure codes were implemented. These methods facilitate efficient and accurate dynamics calculations on a variety of photochemically relevant systems ranging from simulations in the gas phase with high-level XMS-CASPT2 electronic structure (including spin-orbit couplings) to QM/MM simulations in the condensed phase. The second chapter focuses on the energy transfer between an infrared laser and solvated molecules, combining the traditional harmonic approximation to calculate infrared spectra with methods based on \textit{ab initio} molecular dynamics. This methodology is used to elucidate the coherent energy transfer dynamics from the field to the molecule in field-resolved spectroscopic measurements. The third chapter of this thesis surveys the intricate world of 2-enone photochemistry. By exploring $\pi\pi^*$ and $n\pi^*$ reactivity using high-level electronic structure methods, insights are gained into the \textit{Z}/\textit{E} isomerization of cyclohept-2-enone and the photoinduced rearrangement of 5,5-dimethylcyclopent-2-enone to a ketene. In the final chapter, mechanistic investigations are extended to Lewis acid\hyp coordinated enones, uncovering the impact of coordination on the electronic states, UV-Vis spectra, and reactivity. Trajectory surface hopping calculations are used in combination with ultrafast transient absorption spectroscopy to uncover the dynamics of the relaxation of cyclohex-2-enone-BF$_3$ to the reactive triplet states and the photo-induced B\textendash Cl bond dissociation in benzaldehyde-BCl$_3$. Collectively, this work exemplifies the potent synergy of computational and spectroscopic techniques in unraveling photochemical mechanisms. From explicit solvent relaxation to multi-step organic reactions and from spectroscopic signatures to intricate electronic transitions, this thesis advances our understanding of photochemical processes across a spectrum of molecular examples. The findings have implications for the design and understanding of photochemical reactions and spectroscopic studies in complex environments

니켈 및 팔라듐에 의한 광촉매적 탄소–탄소 결합 형성 반응 개발

학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 화학부, 2021. 2. 이홍근.Three C–C bond forming reactions were developed via Ni- and Pd-mediated photocatalysis. Part I introduces C–C bond formation reactions enabled by nickellaphotoredox catalysis. Nickellaphotoredox has emerged as a powerful synthetic tool to achieve novel chemical transformations through the merger of single electron based radical chemistry and two electron based transition metal catalysis using visible light as the energy source. Chapter 1 summarizes the key concepts and strategy in nickellaphotoredox catalysis along with recent achievements with a major emphasis on C–C bond formation. Chapter 2 includes a formal C(sp3)–H Giese addition reaction through nickellaphotoredox catalysis where diverse C–H nucleophiles undergo C–C bond formation with Michael acceptors. A novel pseudo-[2+2] metalation-HAT process was disclosed through a series of control experiments. Finally, chapter 3 describes a direct C–H acylation reaction of unactivated hydrocarbons using amides as the acyl surrogate. In this reaction, catalytic C–H activation occurs before the oxidative addition, enabling unconventional reactivity. This reaction mechanism was fully supported through computational and experimental methods. Part II consists of Pd-mediated photocatalytic reactions where Pd catalysis takes place with the aid of visible light. Unlike conventional Pd catalysis, single electron based radical type pathways predominate in these transformations. Chapter 4 reviews the theoretical concepts of Pd photocatalysis and recent achievements in the field. A series of C–C bond forming reactions was developed with emphasis on employing alkyl electrophiles. While alkyl electrophiles are highly challenging substrates in traditional Pd catalysis due to facile β-hydride elimination, Pd photocatalysis serves to prevent β-hydride elimination through the formation of a Pd(I)/alkyl radical hybrid. Utilizing this strategy, the first intermolecular Heck coupling of unactivated alkyl chlorides has been achieved (Chapter 5). This method enabled the direct Heck couplings of various alkyl chlorides with activated olefin partners. Mechanism studies based on thorough kinetic isotope effect experiments revealed an oxidative pathway, not the previously proposed β-hydride elimination pathway.본 논문에서는 니켈과 팔라듐에 의한 광촉매적 탄소–탄소 결합 형성 반응 세 가지를 다룬다. 첫 부분은 니켈광산화환원 촉매를 통한 탄소–탄소 결합 형성 반응에 관한 연구이다. 니켈광산환원은 빛 에너지를 통해 단전자 기반의 라디칼 화학과 이전자 기반 전이 금속 촉매 반응을 융합하여 다양한 새로운 화학 변환을 수행하는 강력한 전략으로 주목받고 있다. 제 1장은 니켈광산화환원의 기본 전략 및 최신 연구 결과들을 탄소–탄소 결합 형성 반응에 초점을 맞추어 소개한다. 이를 토대로, 니켈광산화환원을 이용한 형식적 C(sp3)–H Giese 첨가 반응을 개발하였다 (2장). 해당 반응에서는 다양한 탄소–수소 결합을 가진 물질들이 마이클 받개와 탄소–탄소 결합을 형성한다. 반응 메커니즘 연구를 통하여 현재까지 유사-[2+2] 금속화-수소 원자 이동 과정이 중요한 역할을 한다는 것을 밝혔다. 또한, 니켈광산화환원 전략을 통하여, 아마이드를 아실원으로부터 비활성 탄소–수소 결합의 직접적인 아실화 반응을 개발하였다 (3장). 여러 통제 실험 및 계산적인 메커니즘 연구를 통하여, 해당 반응에서는 탄소–수소 결합 활성화가 아실원의 산화성 첨가보다 먼저 일어나, 현재까지와는 다른 반응성을 보일 수 있다는 것을 밝힐 수 있었다. 두 번째 부분은 팔라듐에 의해 매개되는 가시광선 촉매 반응에 대하여 다룬다. 일반적인 팔라듐 촉매 반응과는 달리, 해당 반응들은 주로 단전자 과정을 거치게 된다. 제 4장은 팔라듐 광촉매 반응에 대한 전략 및 최신 연구가 논의되었다. 팔라듐 광촉매 반응은 베타-수소 제거 부반응을 억제하며, 열적 팔라듐 촉매 반응에서는 사용하기 어려운 알킬 친전자체의 사용을 가능케 하였다. 이를 기반으로 비활성 염화 알킬의 분자 간 Heck 반응에 대한 연구를 진행하였다 (5장). 동위 원소 효과를 기반으로 한 메커니즘 연구를 통하여, 열적 반응에서 주로 제시되는 베타-수소 제거 반응이 아니라, 단전자 산화 환원이 반응 경로에서 중요한 역할을 한다는 것을 알 수 있었다.Abstract i Table of Contents iii List of Tables vii List of Schemes ix List of Figures xii Appendix 231 Abstract in Korean 335 Part I. Nickellaphotoredox Catalyzed C–C Bond Formation Reactions Chapter 1. Nickellaphotoredox Catalysis and Application to C–C Bond Formation Reactions 1.1 Introduction 1 1.2 General Concepts of Visible Light Photoredox Catalysis 2 1.3 Principles of Nickellaphotoredox Catalysis 4 1.4 Involvement of Activated Alkyl Nucleophiles 6 1.5 Involvement of C(sp3)–H Nucleophiles 14 1.5.1 Involvement of C(sp3)–H Nucleophiles through Direct Single- Electron Oxidation 14 1.5.2 Involvement of C(sp3)–H Nucleophiles through Hydrogen Atom Transfer 17 1.6 Conclusion 23 1.7 References 25 Chapter 2. Formal Giese Addition of C(sp3)–H Nucleophiles Enabled by Visible Light Mediated Ni Catalysis of Triplet Enone Diradicals 2.1 Introduction 29 2.2 Results and Discussion 31 2.2.1 Optimization of Reaction Conditions 31 2.2.2 Substrate Scope 32 2.2.3 Mechanistic Studies 36 2.3 Conclusion 41 2.4 Experimental Section 42 2.4.1 General Information 42 2.4.2 General Procedure for the Formal Giese Reaction 43 2.4.3 Cyclic Voltammetry Study 43 2.4.4 Procedure for the UV Sensitizer Studies 46 2.4.5 Procedure for the Photodimerization Studies 46 2.4.6 Ni Kinetic Order Experiment 48 2.4.7 On/Off Study 49 2.4.8 Quantum Yield Measurement 50 2.4.9 Reaction with Other Lewis or Brønsted Acids 54 2.4.10 α-Deuteration Study 55 2.4.11 Sterm-Volmer Quenching Experiments 57 2.4.12 Procedure for the Competition Experiments 59 2.4.13 Procedure for the Kinetic Isotope Effect Measurements 59 2.4.14 Characterization Data for Products 60 2.5 References 79 Chapter 3. Synergistic Activation of Amides and Hydrocarbons for Direct C(sp3)–H Acylation Enabled by Metallaphotoredox Catalysis 3.1 Introduction 82 3.2 Results and Discussion 85 3.2.1 Reaction Development 85 3.2.2 Mechanistic Studies 87 3.2.3 Substrate Scope 101 3.3 Conclusion 106 3.4 Experimental Section 107 3.4.1 General Information 107 3.4.2 Procedure for the Preparation of N-acylsuccinimides 108 3.4.3 General Procedure for the C(sp3)–H Acylation Reaction 108 3.4.4 Additional Reaction Optimizations 110 3.4.5 Control Experiment with Succinimide 111 3.4.6 Radical Trapping Experiments 112 3.4.7 Procedure for the Sequential Addition Studies 117 3.4.8 Investigation on Ni Precatalysts and Acyl Sources 118 3.4.9 Kinetic Isotope Effect Measurements 119 3.4.10 Synthetic Applications 120 3.4.11 Computational Details 122 3.4.12 Mulliken Spin Densities of Open Shell Ni Complexes 125 3.4.13 TD-DFT Computations 126 3.4.14 Characterization Data for Products 130 3.5 References 144 Part II. Visible Light Mediated Pd Catalyzed C–C Bond Formation Chapter 4. Visible Light Mediated Pd Catalysis and Application to C–C Bond Formation Reactions 1.1 Introduction 149 1.2 Basic Principles of Photoexcited Pd Catalysis 150 1.3 Photoirradiated Pd Catalyzed Cross Coupling Reactions 151 1.4 Photoirradiated Pd Catalyzed Multicomponent Reactions 157 1.5 Conclusion 159 1.6 References 161 Chapter 5. Pd-catalyzed Mizoroki-Heck Coupling of Unactivated Alkyl Chlorides 5.1 Introduction 163 5.2 Results and Discussion 168 5.2.1 Optimization of Reaction Conditions 168 5.2.2 Substrate Scope 169 5.2.3 Mechanistic Studies 176 5.3 Conclusion 185 5.4 Experimental Section 186 5.4.1 General Information 186 5.4.2 General Procedure for the Mizoroki-Heck Reaction 187 5.4.3 E/Z Isomerization Experiment 187 5.4.4 Radical Trapping Experiments 188 5.4.5 Stern-Volmer Quenching Experiment 190 5.4.6 Preparation of Deuterated Substrates 191 5.4.7 Kinetic Isotope Effect Measurements 196 5.4.8 Control Experiments with tert-butyl (N-acyloxy)phthalimides 199 5.4.9 Computational Details 200 5.4.10 Computation of Redox Potentials 201 5.4.11 Kinetic Isotope Effect Computations 202 5.4.12 Time-Dependent Density Functional Theory Computations 203 5.4.13 Characterization Data for Products 204 5.5 References 226 Appendix NMR Spectra Chapter 2 231 Chapter 3 267 Chapter 5 298Docto

Multiproduct terpene synthases: catalytic promiscuity and cyclization of substrate geometric isomers

Terpenes constitute the largest and the most diverse class of natural products. The wealth of terpenes can be attributed to highly promiscuous enzymes called terpene synthases. Apart from single product enzymes, there also exist multiproduct terpene synthases generating a bouquet of acyclic and cyclic products. This thesis is aimed at using substrate analogs to study catalytic promiscuity and mechanistic pathways of multiproduct terpene synthases. The mechanistic details of reaction cascade in TPS4 and TPS5 from Zea mays were evaluated by using isotope sensitive branching. Labeled substrates with deuterium atoms completely surrounding the key cationic intermediates were used as metabolic probes. Apart from the confirmation of mechanistic cascade, kinetic isotope effects on terminating deprotonations led to an enhanced formation of alcohols over olefinic products. Deuterium labeled (2Z)-substrate geometric isomers, mimicking the nerolidyl diphosphate intermediate with TPS4 and TPS5 generated the same product profile but with increased cyclic products. Major increase in enzymatic turnover was also observed with (2Z)-substrates emphasize the rate limiting effect of the initial isomerization step. In contrast, MtTPS5 from Medicago truncatula showed a new product profile with majority of products formed via a C1-C11 ring closure to the humulyl cation over the natural cadalane skeleton. This demonstrates the possibility of using substrate geometry as tool to generate novel products. The structural characteristics of multiproduct terpene synthases remain unresolved due to absence of defined crystal structures. With some initial signs of success as co-crystallization candidates, 3-bromo analogs of substrates were found to be potent competitive inhibitors of MtTPS5 and other terpene synthases. Consequently with this work, catalytic promiscuity of multiproduct terpene synthases can be employed to design better biocatalysts with improved turnover and generate novel products

Boron in Catalysis and Materials Chemistry: A Themed Issue in Honor of Professor Todd B. Marder on the Occasion of His 65th Birthday

Boron, a metalloid with rich chemistry, continues to offer a diverse platform in designing novel catalysts and materials for applications in a variety of areas. This book, while celebrating Professor Todd Marder’s contributions to boron chemistry, on the occasion of his 65th birthday in November 2020, highlights and brings into focus some of the important discoveries in this field, through state-of-the-art reviews and research article