Tesis sobre el tema "Homolysis"

Les alcoxyamines sont des molécules connues pour leur capacité à produire des radicaux via l’homolyse de leur liaison C-ON. Cette homolyse peut être produite par diverses méthodes d’activation, comme par voie thermique, photocatalysée ou encore enzymatique. De plus, il est possible de modifier leur structure de manière exhaustive, afin d’en modifier les propriétés. Toutes ces possibilités permettent d’envisager pour cette famille de composés de nombreuses applications dans des domaines extrêmement variés. Cette thèse présente la synthèse et l’étude physico-chimique d’un certain nombre d’alcoxyamines inédites. Ces dernières ont été développées dans l’objectif d’une meilleure compréhension de leurs modes d’action et d’une amélioration des propriétés recherchées vis-à-vis d’applications innovantes comme la théranostique ou encore des moyens d’activation plus exotiques comme la résonnance plasmonique
Alkoxyamines are molecules well-known for their abilities to generate radicals from C-ON bond homolysis. This homolysis can be induced by various methods like thermally, by photocatalysis or by enzymatic activation. In addition, it is easy to modulate their chemical properties by modifying their structure. Thus we can imagine many various applications for these compounds. Here we will describe the synthesis of new alkoxyamines and investigations about their properties. These alkoxyamines have ben developed in order to acquire new knowledge about their reactivity, but also to improve their structures with respect to innovative applications like theranostic, or some new homolysis pathways like localized plasmon resonance

The preparation of carbocyclic medium rings by two electron processes is reviewed with particular reference to the synthesis of natural products. The formation of medium rings by oxidative and homolytic methods is also reviewed. The synthesis and behaviour of both cis- and tran- ring expansion precursors is described. The 1,4-addition of tributylstannyl lithium to a range of cyclic α,β-unsaturated ketones was performed and procedures found whereby the so-formed enolates could be alkylated with a variety of electrophiles. Using these procedures a range of trans- ring expansion precursors were obtained in moderate to good yield. By the 1,4-addition of tributylstannyl lithium to 2-(ω-phenylselenoalkyl)-cyclohexenones, followed by enolate quenching with either water or methyl iodide, a range of cis- ring expansion precursors were produced. Homolytic ring expansion by either one, three, or four carbon atoms was shown to be possible, producing, respectively, seven, nine, or ten membered functionalised cycloalkenones in high yield except in cases where intramolecular reductive elimination was also possible. Attempts to extend this methodology to the synthesis of exomethylene cycloalkanones is described. The 3-tributylstannyl-3-(ω-phenylselenoalkyl)-cyclohex-2-enone precursors were found not to be successful substrates for ring expansion. The regiospecific alkylation of 2-(tributylstannylmethyl)-cyclohexanone with l-chloro-4-iodo-butane, followed by conversion of the chloride moiety to iodide led to a precursor which, on exposure to homolysis conditions, fragmented to produce the desired exomethylene cyclodecanone in high yield. Work directed towards the synthesis of medium ring cycloalkynones is described. Procedures were developed whereby 2-alkylated cyclohexan-l,3-dione derivatives could be obtained cleanly and in excellent yield on a large scale. The conversion of these derivatives to potential cycloalkynone precursors is described. It is shown that the products obtained after exposure of these precursors to homolysis conditions could, in principle, be derived from the putative cycloalkynones and mechanisms are suggested to explain the formation of these compounds. The homolytic ring expansion reaction was also performed on a substrate possessing an acyl radical precursor in the hope that a medium ring 1,2-dione would be produced. The synthesis of this substrate and its behaviour towards ring expansion is described. It is shown that, again, radical reaction was successful (to the medium ring dione) however subsequent reactions of this product led to the isolation and characterisation of a number of compounds . Attempts to extend this methodology to the synthesis of the natural products curdione and neocurdione is also described. Model reactions with 2,6-dimethylcyclohex-2-enone as the 1,4-addition precursor and 1,4-di-iodobutane as the electrophile led to a ring expansion substrate which fragmented to two ring contracted isomeric compounds in addition to the ring expanded material. Approaches to the preparation of suitable electrophiles for the natural product synthesis are described and their proposed use in subsequent conversion to curdione and neocurdione given.

Certaines diazines-1,4 - en particulier la phénazine – sont susceptibles de provoquer la photo-homolyse de l’eau. Ce travail porte sur les réactions photoinduites de l’octahydro-1,2,3,4,6,7,8,9 phénazine. Après étude par R. P. E. Des diverses espèces radicalaires formées par transfert d’un électron sur cette molécule, nous avons pu montrer que par irradiation des solutions d’octahydrophénazine dans l’eau ou dans l’alcool, c’est le radical cation qui se forme très rapidement : il résulte de l’arrachement d’un atome d’hydrogène par la molécule monoprotonée excitée. C’est surtout l’octahydrophénazine qui fournir cet atome d’hydrogène en milieu aqueux, tandis qu’en milieu alcoolique, c’est le solvant qui est le principal donneur. Le radical résultant de la perte d’un atome d’hydrogène par la molécule de départ redonne principalement le produit initial en arrachant un atome d’hydrogène au solvant, ce qui conduit à la formation d’eau oxygénée ou d’une cétone. Il peut également donner des produits d’addition ou évoluer vers la tétrahydro-1,2,3,4 phénazine. Le mécanisme proposé met en évidence le rôle particulier joué par les hydrogènes cyclohexaniques en α du noyau pyrazinique de la molécule.

La réactivité de l’α-bromoacrylate d’éthyle et du benzylidène malonate d’éthyle vis à vis des dialkylzincs en milieu aérobie a été étudiée afin d’évaluer la capacité des radicaux α-alcoxycarbonyle tertiaires à évoluer par SH2 sur le métal pour conduire à un énolate de zinc. Le travail expérimental réalisé à partir de l’α-bromoacrylate d’éthyle a permis la synthèse de cyclopropanes et de céto-esters. Dans le cas des benzylidène malonates la réversibilité de l’addition du diéthylzinc sur le substrat, a été mise en évidence. L’effet inhibiteur d’additifs tels que TMSCl ou CuCl concourt à indiquer que les peroxydes de zinc formés dans le milieu pourraient y tenir un rôle clé. L’étude théorique a mis en évidence pour les 2 substrats étudiés, le rôle crucial de la stabilisation de l’énolate formé sous la forme d’un chélate à 5 ou 6 chaînons. Les carbozincations d’ynamides via le CuI ou le FeCl2 en présence de dialkylzincs ont été étudiées pour la synthèse régio-et stéréosélective d'énamides tri- ou tétrasubstitués. Le CuI s’est montré plus performant et moins substrat-dépendant que FeCl2. Une étude théorique a été réalisée afin de mieux comprendre ce phénomène. Enfin, l'addition intermoléculaire des radicaux sulfanyle sur les ynamides a été revisitée. Les calculs théoriques et les résultats expérimentaux montrent que la régio- et stéréosélectivité de la réaction dépendent de la nature du substituant porté par le carbone en β de l’atome d’azote et des conditions expérimentales. L’addition intermoléculaire inédite d’un radical carboné électrophile sur ces substrats a pu être décrite et ouvre de nouvelles perspectives quant à la synthèse d’énamides tétrasubstitués originaux
The reactivity of ethyl α-bromoacrylate and ethyl benzylidene malonate towards dialkylzincs in aerobic medium was studied in order to evaluate the capacity of tertiary α-alcoxycarbonyl radicals to undergo SH2 at zinc leading to a zinc enolate. The use of ethyl α-bromoacrylate allowed the synthesis of cyclopropanes and keto-esters. With the second substrate, the addition of the alkyl group was shown to be reversible. The inhibitor effect of additives like TMSCl or CuCl suggested that zinc peroxydes formed in situ could play a key role in the process. Theoretical studies highlighted the crucial role of the stabilization of the zinc enolate through the formation of a 5 or 6-membered chelate. Regio- and stereoselective synthesis of tri- and tetra-substituted enamides was achieved through the carbozincation of ynamides in the presence of dialkylzincs and CuI or FeCl2 as catalyst. CuI was shown to be more efficient and less substrate-dependent than FeCl2. Molecular modelings were performed to better understand this phenomen. Finally, intermolecular addition of sulfanyl radicals onto ynamides was revisited. Theoretical calculations and experimental results showed that the regio- and stereo-selectivity of the process depended on the nature of the substituent on the carbon in β position of the nitrogen atom and on experimental conditions. Unprecedented intermolecular addition of a carbon-centered radical has been described and opened new perspectives for the synthesis of original tetrasubstituted enamides

Avec le développement des concepts de la chimie verte, il est devenu nécessaire de remplacer les métaux toxiques par des composés plus respectueux de l’environnement. Donneurs d’hydrogène pour des réactions radicalaires, les hydrures de trialkylétain sont encore très utilisés. Les NHC-boranes se sont révélés de bons remplaçants pour les réactions de désoxygénation. Cependant, les réactions de déshalogénation effectuées avec des NHC-boranes sont moins efficaces et il a fallu avoir recours au concept de catalyse à polarité inversée. Ces travaux ont été le point de départ de cette thèse où la synthèse de nouveaux NHC-boranes possédant une liaison B-S ou B-N est développée. L’étude des propriétés de ces nouveaux complexes a été effectuée et des applications en chimie organique et en science des polymères ont été trouvées. Par ailleurs, en vue d’étudier les effets polaires sur la formation et la réactivité des radicaux boryles, une nouvelle famille de carbène-boranes a été synthétisée
Along with the development of green chemistry, it became necessary to avoid toxic metallic complexes in organic reactions and replace them by more sustainable compounds. An hydrogen donors for radical reactions, trialkylstannanes are still widely used. NHC-boranes seem to be good substitutes for deoxygenation reactions. However, dehalogenation reactions are less effective and polar reversal catalysis was used. This work was the starting point of this Ph.D thesis where the synthesis of new NHC-boranes bearing a B-S or B-N bound is developed. The study of the properties of these new complexes was performed and applications in organic chemistry as well as in polymer science were found. Besides, to study polar effects on the formation and on the reactivity of boryl radicals, a new family of carbene-boranes was synthesized

La réactivité de l’α-bromoacrylate d’éthyle et du benzylidène malonate d’éthyle vis à vis des dialkylzincs en milieu aérobie a été étudiée afin d’évaluer la capacité des radicaux α-alcoxycarbonyle tertiaires à évoluer par SH2 sur le métal pour conduire à un énolate de zinc. Le travail expérimental réalisé à partir de l’α-bromoacrylate d’éthyle a permis la synthèse de cyclopropanes et de céto-esters. Dans le cas des benzylidène malonates la réversibilité de l’addition du diéthylzinc sur le substrat, a été mise en évidence. L’effet inhibiteur d’additifs tels que TMSCl ou CuCl concourt à indiquer que les peroxydes de zinc formés dans le milieu pourraient y tenir un rôle clé. L’étude théorique a mis en évidence pour les 2 substrats étudiés, le rôle crucial de la stabilisation de l’énolate formé sous la forme d’un chélate à 5 ou 6 chaînons. Les carbozincations d’ynamides via le CuI ou le FeCl2 en présence de dialkylzincs ont été étudiées pour la synthèse régio-et stéréosélective d'énamides tri- ou tétrasubstitués. Le CuI s’est montré plus performant et moins substrat-dépendant que FeCl2. Une étude théorique a été réalisée afin de mieux comprendre ce phénomène. Enfin, l'addition intermoléculaire des radicaux sulfanyle sur les ynamides a été revisitée. Les calculs théoriques et les résultats expérimentaux montrent que la régio- et stéréosélectivité de la réaction dépendent de la nature du substituant porté par le carbone en β de l’atome d’azote et des conditions expérimentales. L’addition intermoléculaire inédite d’un radical carboné électrophile sur ces substrats a pu être décrite et ouvre de nouvelles perspectives quant à la synthèse d’énamides tétrasubstitués originaux
The reactivity of ethyl α-bromoacrylate and ethyl benzylidene malonate towards dialkylzincs in aerobic medium was studied in order to evaluate the capacity of tertiary α-alcoxycarbonyl radicals to undergo SH2 at zinc leading to a zinc enolate. The use of ethyl α-bromoacrylate allowed the synthesis of cyclopropanes and keto-esters. With the second substrate, the addition of the alkyl group was shown to be reversible. The inhibitor effect of additives like TMSCl or CuCl suggested that zinc peroxydes formed in situ could play a key role in the process. Theoretical studies highlighted the crucial role of the stabilization of the zinc enolate through the formation of a 5 or 6-membered chelate. Regio- and stereoselective synthesis of tri- and tetra-substituted enamides was achieved through the carbozincation of ynamides in the presence of dialkylzincs and CuI or FeCl2 as catalyst. CuI was shown to be more efficient and less substrate-dependent than FeCl2. Molecular modelings were performed to better understand this phenomen. Finally, intermolecular addition of sulfanyl radicals onto ynamides was revisited. Theoretical calculations and experimental results showed that the regio- and stereo-selectivity of the process depended on the nature of the substituent on the carbon in β position of the nitrogen atom and on experimental conditions. Unprecedented intermolecular addition of a carbon-centered radical has been described and opened new perspectives for the synthesis of original tetrasubstituted enamides

The critically important nature of radical and radical ion mechanisms in biology and chemistry continues to be recognized as our understanding of these unique transient species grows. The work presented herein demonstrates the versatility of kinetic studies for understanding the elementary chemical reactions of radicals and radical ions. Chapter 2 discusses the use of direct ultrafast kinetics techniques for investigation of crucially important enzymatic systems; while Chapter 3 demonstrates the value of indirect competition kinetics techniques for development of synthetic methodologies for commercially valuable classes of compounds. The mechanism of decay for aminyl radical cations has received considerable attention because of their suspected role as intermediates in the oxidation of tertiary amines by monoamine oxygenases and the cytochrome P450 family of enzymes. Radical cations are believed to undergo deprotonation as a key step in catalysis. KIE studies performed by previous researchers indicate N,N-dimethylaniline radical cations deprotonate in the presence of the bases acetate and pyridine. By studying the electrochemical kinetics of the reaction of para substituted N,N-dimethylaniline radical cations with acetate anion, we have produced compelling evidence to the contrary. Rather than deprotonation, acetate reacts with N,N-dimethylaniline radical cation by electron transfer, generating the neutral amine and acetoxyl radical. Transport properties of reactants and solvent polarity changes were investigated and confirmed not to influence the electrochemical behavior forming the basis for our mechanistic hypothesis. To reconcile our conclusion with earlier results, KIEs were reinvestigated electrochemically and by nanosecond laser flash photolysis. Rather than a primary isotope effect (associated with C-H bond cleavage), we believe the observed KIEs are secondary, and can be rationalized on the basis of a quantum effect due to hyperconjugative stabilization in aromatic radical cations during an electron transfer reaction. Product studies performed by constant potential coulometry indicate N,N-dimethylaniline radical cations are catalytic in carboxylate oxidations. Collectively, our results suggest that aminyl radical cation deprotonations may not be as facile as was previously thought, and that in some cases, may not occur at all. Interest in design and synthesis of selenium containing heterocycles stems from their ability to function as antioxidants, anti-virals, anti-inflammatories, and immunomodulators. To establish synthetic feasibility of intramolecular homolytic substitution at selenium for preparation of selenocycles, we set out to determine what factors influence cyclization kinetics. A series of photochemically labile Barton and Kim esters have been syntheisized and employed as radical precursors. The effect of leaving radical stability on kinetics has been investigated through determination of rate constants and activation parameters for intramolecular homolytic substitution of the corresponding radicals via competition experiments. Notable leaving group effects on measured kinetic parameters show more facile reactions for radical precursors with more stable leaving radicals. Moreover, cyclizations to form six-membered (as opposed to five- membered) ring systems exhibited order of magnitude decreases in rate constants for a given leaving radical. Our results are congruent with expectations for radical cyclizations trends for the varied experimental parameters and suggest homolytic substitution affords a convenient means for synthesis of selenocycles.
Ph. D.

Deux nouveaux concepts, visant à reproduire la chimie radicalaire des diétains à l’aide de radicaux centrés sur le silicium, sont présentés à travers ce manuscrit. Le premier concept introduit les “silaboranes”, des molécules constituées d’un motif de type silane et d’un atome de bore. Ceux-ci ont pour la première fois été exploités comme générateurs de radicaux triméthylsilyle via l’utilisation de la réaction de SHi sur le silicium (Substitution Homolytique Intramoléculaire) à partir de disilanes. Des études cinétiques et de modélisation moléculaires de la réaction de SHi ont, entre autres, permis de rationaliser les résultats. Le potentiel des “silaboranes” en tant que substituts des diétains a été entrevu à travers des réactions d’additions radicalaires d’halogénures sur des éthers d’oxime sulfonylés. Le concept des "silaboranes" a ensuite été étendu à des hydrures de silicium, grâce à une réaction de transfert d’hydrogène intramoléculaire, permettant de produire des radicaux triphénylsilyles. Le second concept a révélé la capacité des allyl tris(triméthylsilyl)silanes pour reproduire les réactions radicalaires des diétains via une réaction de beta-fragmentation du groupement tris(triméthylsilyle). Ces substrats, source de radicaux tris(triméthysilyle) et simples d’accès, se sont avérés d’intéressants candidats pour assister l’addition de dérivés bromés et iodés sur des substrats sulfonylés de type allyl, vinyl et éther d’oxime
Two new concepts, aiming to substitute ditin radical chemistry by using silyl radicals, are developed throughout this manuscript. The first concept introduces “silaboranes”, molecules made up of a silane unit and a boron atom. For the first time, the ability of these precursors to generate trimethylsilyl radicals was demonstrated by using the SHi reaction at silicon (Intramolecular Homolytic Substitution) from disilanes. Besides, results are supported by kinetic and computationnal studies of the SHi reaction at silicon. Capacity of “silaboranes” to achieve tin-free radical processes was demonstrated thanks to radical addition of halogenated species on sulfonyl oxime ethers. “Silaboranes” concept was then extended to silicon hydrides using intramolecular hydrogen transfer as source of triphenylsilyl radicals. The second concept highlights the ability of allyl tris(trimethylsilyl)silanes to make possible tin-free radical reactions via beta-fragmentation of the tris(trimethylsilyl) group. These compounds, source of tris(trimethylsilyl) radicals and easily available, open very interesting perspectives in tin-free radical addition of bromides and iodides species on sulfonyl derivatives as allyl sulfones, vinyl sulfones or sulfonyl oxime ethers

碩士
國立東華大學
物理學系
106
After binding the substrate, lysine 5,6 aminomutase change the 3D construction from open state to close state, and start to catalyze. The beginning of the catalysis is the hemolysis of Co-C bond in adenosylcobalanine. When 5,6 LAM changed to close state, the Glu411 play an important role at the beginning of the catalysis. As the life time of close state is very short, the 3D construction of 5,6 LAM cannot be observed directly nowadays. In 2018, Sandeep Kumar simulated the close state construction of 5,6 LAM by bio-information comparison. This result reveals that Glu411 has contribution of electrostatic energy of Co-C hemolysis. This construction shows the distance of from the hydroxide of glutamate to hydroxide on ribose of AdoCbl is nearly 3Å. This research use site-directly mutagenisis to change Glu411 into glutamine, aspartic acid, and alanine. According to the distanece of polar side chain of amino acid, electro force will decrease E411Q > E411D > E411A. And the ability of catalysis should be E411Q > E411D > E411A. Kcat /Km of E411D is about 500-fold decrease compare to wild type. E411A and E411Q cannot observe any activity at all. Alanine is a small amino acid. The change from glutamate to alanine is too big. And this may probabily change the whole 3D construciton of 5,6 LAM, leading protein lose activity. It is very difficult to explain why E411Q lose activity and E411D have activity. In the futrue, we’ll change adenosine into 2’-3’deoxyadenosine by chamical synthesis. It can be more directly to observe how Glu411 contribute to the adensine.

Part I. The radical chemistry of geminal bis-azoalkanes. Two geminal bis-azoalkanes have been employed to generate carbon centered radicals adjacent to azo substituents. The activation free energies for C-N bond homolysis of 2,2-bis-(phenylazo)propane (1) and 2-methylazo-2-phenylazopropane (2) were 8 kcal/mol lower than for the corresponding model compounds 3-methyl-3-phenylazo-1-butene (4) and 3-methyl-3-methylazo-1-butene (5). This large rate enhancing effect of an $\alpha$-phenylazo substituent is ascribed to the high energy of azo functional groups. 2-(Phenylazo)-2-propyl radical was easily trapped by good hydrogen donors such as thiophenol to afford a hydrazone. The interconversion of geminal bis-azoalkane 2 and tetrazene 3 by low temperature photolysis has been observed. Part II. The radical chemistry of vicinal bis-azoalkanes. Three vicinal bis-azoalkanes have been synthesized by oxidation of hydrazones. In thermolysis, substituents on the azo group dramatically influence the bond homolysis pattern, which varies from pure C-C homolysis when the substituent is phenyl to pure C-N homolysis in the case of a t-butyl substituent. Phenylazo accelerates $\beta$ C-C bond homolysis by approximately 3.2 kcal/mol more than the methylazo group. This result supports the delocalized $\pi$ electronic structure of the 2-(phenylazo)-2-propyl radical. The photochemical behavior of vicinal bis-azoalkanes resembles that of mono azoalkanes except for 9, which underwent both C-C and C-N bond homolysis. $\beta$-Azo radicals from stepwise C-N bond homolysis have been clearly trapped. Part III. Homolysis of a weak C-C bond. The formal para-recombination product of 2-methoxycarbonylpropyl and trityl radicals (53) was readily air oxidized to hydroperoxide through a radical chain mechanism. The weak C-C bond in 53 was cleaved homolytically in thermolysis, photolysis, and triplet sensitized photolysis generating methyl isobutyrate radical and triphenylmethyl radical. This result rules out McElvain's concerted thermolysis mechanism. Triphenylmethyl radical underwent intramolecular cyclization under the photolysis conditions. The facile aromatization of 53 through a radical mechanism was observed.

Part I. The tritium isotope effect for hydrogen atom abstraction by the 1-adamantyl radical in cyclohexane was determined to be 103, confirming the exceptionally large deuterium isotope effect found earlier for this process. While the Noyes model accounts for the cage effect in the thermolysis of cis -1-azoadamantane, the non-linear correlation between the yield of cage dimer and solvent fluidity at high viscosities suggests that microviscosity influences the breakdown of the solvent cage. In acetonitrile, 1-adamantyl radicals were found to abstract hydrogen atoms or to add to the nitrile function. The products of cross-recombination between the resulting radicals were identified and quantified. Part II. The carbon-centered $\beta$-azo radical was calculated to fragment under formation of nitrogen with an exothermicity of $\sim$10 kcal/mole. The generation of such a $\beta$-azo radical was attempted by homolytic fragmentation of five acyclic and cyclic $\beta$-substituted azo compounds. Although concerted decomposition of these compounds could cause a drastic rate enhancement, our azo compounds exhibited only a slight rate enhancement (1.5-9 fold) in comparison to the unsubstituted azo compounds. The radical stability of the $\beta$-substituent exerted no influence on the rate of azo fragmentation. The high temperature required for pyrolyses (180$\sp\circ$C) led to complicated product mixtures due to competing bond scission between the azo moiety and the $\beta$-substituent, as well as the decomposition of primary thermolysis products. For $\beta$-azo phosphinites and $\beta$-azo carbonates, the fragmentation was governed by both ionic and radical processes. The tin hydride reduction of a cyclic $\beta$-azo xanthate at room temperature proceeded via intramolecular radical attack on the azo linkage to yield an unusual cyclic thiourea rather than by loss of N$\sb 2$.

Cette thèse de doctorat porte sur la catalyse à partir de métaux de transition et sur la substitution homolytique aromatique favorisée par une base visant à former de nouvelles liaisons C–C, et à ainsi concevoir de nouvelles structures chimiques. Au cours des vingt dernières années, des nombreux efforts ont été réalisés afin de développer des méthodologies pour la fonctionnalisation de liens C–H, qui soient efficaces et sélectives, et ce à faible coût et en produisant le minimum de déchets. Le chapitre d'introduction donnera un aperçu de la fonctionnalisation directe de liens C–H sur des centres sp2 et sp3. Il sera également discuté dans cette partie de certains aspects de la chimie radicalaire reliés a ce sujet. Les travaux sur la fonctionnalisation d’imidazo[1,5-a]pyridines catalysée par des compleces de ruthénium seront présentés dans le chapitre 2. Malgré l'intérêt des imidazo[1,5-a]azines en chimie médicinale, ces composés n’ont reçu que peu d'attention dans le domaine de la fonctionnalisation de liens C–H. L'étendue de la réaction et l'influence des effets stériques et électroniques seront détaillés. Les cyclopropanes représentent les 10ème cycles carbonés les plus rencontrés dans les petites molécules d’intérêt pharmacologique. Ce sont aussi des intermédiaires de synthèse de choix pour la création de complexité chimique. Malgré de grands progrès dans le domaine de la fonctionnalisation de liens C(sp3)–H, l'étude des cyclopropanes comme substrats dans les transformations directes est relativement nouvelle. Le chapitre trois présentera l'arylation intramoléculaire directe de cyclopropanes. Cette réaction est réalisée en présence de palladium, en quantité catalytique, en combinaison avec des sels d’argent. Des études mécanistiques ont réfuté la formation d'un énolate de palladium et suggéreraient plutôt une étape de métallation - déprotonation concertée. En outre, les cycles de type benzoazepinone à sept chaînons ont été synthétisés par l'intermédiaire d'une séquence d'activation de cyclopropane/ouverture/cyclisation. Une arylation directe intermoléculaire des cyclopropanes a été réalisée en présence d'un auxiliaire de type picolinamide (Chapitre 4). Les deux derniers chapitres de ce mémoire de thèse décriront nos études sur la substitution homolytique aromatique favorisée par une base. Le mécanisme de la réaction de cyclisation intramoléculaire d'halogénures d'aryle, réalisée en présence de tert-butylate de potassium, a été élucidé et se produit via une voie radicalaire (Chapitre 5). La transformation, exempte de métaux de transition, ne nécessite que la présence d’une base et de pyridine comme solvant. Cette réaction radicalaire a été étendue à la cyclisation d'iodures d'alkyle non activés en présence d'un catalyseur à base de nickel et de bis(trimethylsilyl)amidure de sodium comme base (Chapitre 6). Des études de RMN DOSY ont démontré une association entre le catalyseur, la base et le matériel de départ.
The dissertation will focus on transition metal catalysis and base-promoted homolytic aromatic substitution as a means of forming new C–C bonds, and thus designing new chemical scaffolds. During the last twenty years, tremenduous efforts have been expended to achieve low-cost, waste-free, efficient and selective C–H bond functionalization methodologies. The introductory chapter will provide an overview of direct functionalization of C–H sp2 and sp3 centers, as well as discuss relevant topics in radical chemistry. Work on the ruthenium-catalyzed functionalization of imidazo[1,5-a]pyridines will be presented in Chapter 2. Despite interest from the medicinal chemistry field, imidazo[1,5-a]azines have received little attention in the C–H functionalization field. The scope of the reaction and, in particular, the influence of sterics and electronics will be detailed. Cyclopropanes represent the 10th most encountered rings in small drug synthesis. They are also valuable synthetic intermediates en route to more chemical complexity. Despite great advances in the field of C(sp3)–H functionalizations, the exploration of cyclopropanes as substrates in direct transformations is relatively novel. Chapter three will present the intramolecular direct arylation of cyclopropanes. A combination of palladium catalysis in presence of a silver salt was found to mediate the reaction. Mechanistic studies disproved the formation of a palladium-enolate and pointed towards a concerted metalation-deprotonation pathway. Furthermore, seven-membered benzoazepinone rings were synthesized via a cyclopropane activation/opening/cyclization sequence. An intermolecular direct arylation of cyclopropanes was achieved in presence of a picolinamide auxiliary (Chapter 4). The last two chapters of the thesis will describe our studies on base-promoted homolytic aromatic substitution. A potassium tert-butoxide-promoted intramolecular cyclization of aryl halides was shown to occur through a radical pathway (Chapter 5). The transition metal-free transformation occurred in the sole presence of the base and pyridine as the solvent. The radical process was extended to the cyclization of unactivated alkyl iodides in presence of a nickel catalyst and sodium hexamethyldisilzide as the base (Chapter 6). DOSY NMR studies demonstrated an association between the catalyst, base and starting material.

碩士
國立中興大學
化學系所
106
In this study, paramagnetic NMR spectroscopy, X-ray diffraction, magnetic susceptibility and DFT calculation are employed to elucidate the strong bonding interaction between iron(III) dx2-y2 and porphyrin a2u orbitals of [Fe(OMTPP∙)Cl]SbCl6 and [Fe(OETPP∙)Cl]SbCl6. Their crystal structures clearly indicate that their saddle deformations are increased compared to those prior to oxidations. Their 1H NMR data present the S = 2 states for such one-electron oxidation states, and demonstrate that their structures in solutions remain strong saddle deformations. In light of 1H NMR spectroscopy of [Fe(TPP∙)Cl]SbCl6 resembling to the above cases, we postulate that the ring structure of [Fe(TPP∙)Cl]+ may possess strongly saddle to have great bonding interaction between iron(III) dx2-y2 and porphyrin a2u orbitals. In the DFT calculations, the degrees of phenyl ring rotation and saddled deformation will also affect their NMR spectra. In another topic, we observe O-O bond homolytic cleavage of (OETPP)FeIIIO(H)OtBu formed in the reaction of Fe(OETPP)ClO4 with TBHP and its activation parameters (ΔH≠ = 47(2) kJ mol-1, ΔS≠　= 83(9)J mol-1K-1) is measured by low-temperature UV-vis spectral data. The corresponding one-electron oxidation product is identified as [Fe(OETPP∙)OH]+, which is an isoelectronic structure as oxoiron(IV) porphyrin, by UV-vis, NMR spectroscopy and ESI-MS spectrometry. According to the experiments of NMR and ESI-MS, we also find that ·OtBu radical will convert Fe(OETPP)ClO4 to [Fe(OETPP∙)OtBu]+. Furthermore, these related iron(III) porphyrin radical cations can be carried out one more electron oxidation to isoporphyrins, an isoelectronic structure as Compound I. These iron(III) saddled isoporphyrins are shown to be reactive for highly selective chlorination of cyclohexene.

Boronic acid(esters) have been well recognized as an indispensable coupling partner in the Suzuki-Miyaura cross coupling reactions producing a vast spectrum of molecules, applicable in the diverse field ranging from medicinal to materials sciences.[1] Transition metal catalyzed synthesis of boronic esters from diborons with the assistance of bases is a well-established methodology[2]. In this thesis, the cobalt-N-Heterocyclic carbene complexes catalyzed borylation of organic compounds and interaction of diazabutadienes with diboron compounds will be discussed. (i) In the first section, Co(IMes)2Cl2 catalyzed borylation of aryl halides will be discussed. [3a] The robust protocol, operating under mild condition facilitate the borylation of a diverse range of aryl halides with great efficacy, which includes the challenging aryl chlorides. The preliminary mechanistic studies suggest that base-bis(pinacolato)diboron adduct reduces the Co(IMes)2Cl2 complex to generate Co(IMes)2Cl complex, which acts as an active catalytic species. (ii) The second section deals with catalytic synthesis of primary and secondary alkyl boronic esters using alkyl halides. [3b] The in situ generated Co-NHC complex, in assistance with base and diboron compound, produces the corresponding borylated product from alky halides. The reaction proceeds under very mild conditions and covers a wide range of alkyl halides, including chlorides having different functional groups. (iii) In the third section, development in selective hydroboration of vinyl arenes and aliphatic alkenes will be discussed. [3c] Catalyzed by Co(I)NHC complex, the alkene hydroboration by pinacol borane gives Markovnikov selective product with good selectivity, where the regio-selectivity is controlled by phenyl substituent. In absence of that, complete inversion in the selectivity has been observed. The preliminary mechanistic cycle suggests that the catalytic cycle proceeds via oxidative addition of pinacol borane to [Co] followed by alkene insertion and reduction elimination steps. (iv) The last section discusses the interaction of diazabutadiene molecules with diboron compounds. [3d] The diazabutadiene derivatives have been observed to completely cleave the B-B bond of Bis(catacolato)diboron and Bis(dithiocatacolato)diboron. The preliminary findings hint towards homolytic cleavage of the B-B bond by concerted interaction of the two nitrogen atoms of diazabutadiene with the two boron atoms of the diboron from the same face. References: [1] Boronic Acids-Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011. [2] Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.; Marder, T. B. Diboron(4) Compounds: From Structural Curiosity to Synthetic Workhorse. Chem. Rev. 2016, 116, 9091-9161. [3] (a) Verma, P. K.; Mandal, S.; Geetharani, K. ACS Catal. 2018, 8, 4049-4054. (b) Verma, P. K.; Prasad, K. S.; Varghese, D.; Geetharani, K. Org. Lett. 2020, 22, 4, 1431-1436. (c) Verma, P. K.; Setulekshmi, A. S.; Geetharani, K. Org. Lett. 2018, 20, 7840-7845. (d) Verma, P. K.; Meher, N. K.; Geetharani, K. Accepted for publication in Chem. Commun., Manuscript ID: CC-COM-06-2021-002881.R2.

Introduction N-heterocyclic carbenes (NHC) are strong  donors and weak acceptors. Also, NHC forms strong metal-carbon bonds in metal complexes and hence complexes bearing NHC ligands are in general, thermally stable. Chemistry of NHCs and their transition metal complexes has been explored extensively in catalysis. Metal hydride or dihydrogen complexes are reactive intermediates and also employed as catalysts in several catalytic reactions such as hydrogenation, transfer hydrogenation, and hydroformylation. The binding of H2 to a metal center and its cleavage for the oxidative addition to a metal center are key steps in these catalytic reactions. There has been a substantial development in the field of dihydrogen chemistry. In particular, elongated dihydrogen complexes are of significant interest due to their relevance in hydrogenation reactions. A large number of elongated dihydrogen complexes have been reported. However, there has been no systematic study for the elongation of the H–H bond in dihydrogen complexes employing NHC’s as a co-ligand. Objectives The objectives of this work are as follows: i. Synthesis and characterization of ruthenium dihydrogen complexes bearing an NHC ligand. ii. Systematic variation in the ligand environment around a metal center for the elongation of the H‒H bond in the process of oxidative addition of H2 to a metal center. iii. To synthesize new ruthenium hydride and dihydride complexes and explore their activities in catalysis such as hydrogenation, hydrodehalogenation, and CO2 activation. Significant results A series of dihydrogen complexes bearing NHC ligands of the type [RuCl(η2–H2)(CO)(IMes)(PPh3)(L)](OTf) [L = pyridine (Py), 4-methylpyridine (4MePy), acetonitrile (MeCN), pivalonitrile (Me3CCN)] have been prepared by the protonation of hydride complexes [RuHCl(CO)(IMes)(PPh3)(L)] (L = Py, 4MePy, MeCN, Me3CCN) with HOTf. The ligands (Py, 4MePy, MeCN, Me3CCN) trans to the hydride were found to be labile in all the hydride complexes. The H–H bond distances in the η2–H2 ligands of dihydrogen complexes were found to be temperature dependent. The H–H bond distances got slightly elongated (0.98-0.93 Å) with an increase in the temperature (183-233 K). Phosphine analogues, [RuCl(η2–H2)(CO)(PPh3)2(L)](OTf) [L = Py, 4MePy) of NHC dihydrogen complexes were also synthesized. The H‒H bond distances were temperature invariant (0.93 Å, 223-263 K) in these complexes. A series of homobimetallic ruthenium hydride [{RuHCl(CO)(IMes)(PPh3)}2(NN)] (NN= 4,4′-bpy, 4,4′-dpyen, 4,4′-dpyan) [4,4′-bipyridine (4,4′-bpy); 1,2-bis(4-pyridyl)ethylene (4,4′-dpyen); 1,2-bis(4-pyridyl)ethane) (4,4′-dpyan)] complexes bearing an NHC ligand and their corresponding dihydrogen complexes of the type [{RuCl(η2–H2)(IMes)(PPh3)(CO)}2(NN)][OTf]2 (NN= 4,4′-bpy, 4,4′-dpyen, 4,4′-dpyan) have been synthesized and characterized. They are the first examples of homobimetallic dihydrogen complexes bearing NHC ligands. In addition, hydrogenation of internal and terminal alkenes was carried out using these homobimetallic hydride complexes. NHC/PMe3 based cationic complexes of the type [RuH(CO)(IMes)(PMe3)3](X) (X = Cl, BPh4) have been synthesized and characterized using NMR spectroscopy. Partial hydrodechlorination of CHCl3 to CH2Cl2 was observed in the presence of both the complexes. In addition, these complexes were also found to be efficient for the activation of the C‒Cl bond in CH2Cl2 to form [CH2Cl.PMe3]Cl salt in the presence of excess PMe3. Notably, HD exchange in H2 molecules via CDCl3 was observed in the presence of both the complexes. A new and efficient route has been developed for the synthesis of the ruthenium dihydride complexes [Ru(H)2(CO)(L)(PPh3)2] (L = IMes, IPr, PPh3). The reaction pathway for the synthesis of these derivatives was established by isolation of few intermediates. Insertion of CO2 into one of the Ru‒H bond of [Ru(H)2(CO)(L)(PPh3)2] (L = IMes, IPr) complexes took place to afford bidentate formate complexes [RuH(η2-O2CH)(CO)(L)(PPh3)2] (L = IMes, IPr). Structure formulation of these complexes was done using NMR spectroscopy.

Includes bibliographical references.
381 p. ;
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
A comprehensive study into the design, understanding and utilisation of free-radical homolytic substitution chemistry
Thesis (D.Sc.)--University of Adelaide, Dept. of Chemistry, 2000?

Les cyclopropanes sont des unités qui sont très importantes en raison de leur présence dans de nombreux produits naturels, dans certaines molécules synthétiques ayant une activité biologique, ainsi que dans plusieurs intermédiaires synthétiques. Les travaux décrits dans cet ouvrage portent sur l’halogénocyclopropanation stéréosélective d’alcools allyliques en présence d’un ligand chiral stœchiométrique de type dioxaborolane et de carbénoïdes de zinc substitués dérivés de composés organozinciques et d’haloformes. Nous avons ainsi développé des conditions pour l’iodo-, la chloro- et la fluorocyclopropanation stéréosélective. Une étude mécanistique portant sur la nature des carbénoïdes alpha-chlorés et alpha-bromés a révélé qu’il y a un échange des halogènes portés par ces carbénoïdes. Lors de la chlorocyclopropanation, le carbénoïde le plus réactif (alpha-chloré) réagit de façon prédominante en vertu du principe de Curtin-Hammet. Les iodocyclopropanes énantioenrichis ont pu être fonctionnalisés via une réaction d’échange lithium-iode suivie du traitement avec des électrophiles, ou via une réaction de transmétallation au zinc suivie d’un couplage de Negishi. Ainsi, toute une gamme de cyclopropanes 1,2,3-substitués énantioenrichis a pu être synthétisée. Dans l’optique de développer de nouvelles méthodologies de fonctionnalisation des cyclopropanes, nous nous sommes par la suite tournés vers le couplage croisé de type Hiyama-Denmark des cyclopropylsilanols. Dans cette voie synthétique, le groupement silanol a deux fonctions : il sert de groupement proximal basique lors de la cyclopropanation de Simmons-Smith et il subit la transmétallation au cours du couplage croisé. Dans l’étape du couplage croisé, la nature des ligands liés à l’atome de silicium s’est avérée cruciale au bon déroulement de la réaction. Ainsi, l’échange de ligands avec le diéthyl éthérate de trifluoroborane générant le cyclopropyltrifluorosilane in situ est requis pour obtenir de bons rendements. Le dernier volet de cet ouvrage porte sur la cyclisation d’iodures d’alkyle par substitution aromatique par voie homolytique catalysée par le nickel. Une série de composés de type tétrahydronaphtalène et thiochromane ont été préparés selon cette méthode. Une étude mécanistique a confirmé la nature radicalaire de cette réaction et suggère fortement l’action catalytique du nickel. De plus, des études de spectrométrie RMN DOSY ont montré une association entre le complexe de nickel et le substrat ainsi que la base employés dans cette réaction.
Cyclopropanes are important subunits because of their presence in numerous bioactive natural products and synthetic molecules as well as synthetic intermediates. In this work we have investigated the stereoselective halocyclopropanation of allylic alcohols using a dioxaborolane-type stoichiometric chiral ligand and substituted zinc carbenoids derived from organozinc compounds and haloforms. We have thus developed conditions for the stereoselective iodo-, chloro- and fluorocyclopropanation reactions. A mechanistic study on the nature of alpha-chloro and alpha-bromomethylzinc carbenoids has revealed that halogen scrambling is taking place in the case of these carbenoids. During the chlorocyclopropanation reaction, the most reactive carbenoid (alpha-chloromethyl zinc) reacts predominantly, in line with the Curtin-Hammet principle. The enantioenriched iodocyclopropanes have been functionalized through a lithium-iodine exchange followed by treatment with electrophiles or transmetallation to zinc and Negishi cross-coupling. Therefore, a wide array of enantioenriched 1,2,3-substituted cyclopropanes have been synthesized using these methods. In order to develop new methodologies for the functionalization of cyclopropanes, we have studied the Hiyama-Denmark cross-coupling of cyclopropylsilanols. In this approach, the silanol group bears two functions: it serves as a proximal basic group in the Simmons-Smith cyclopropanation and it is involved in the transmetallation event during the cross-coupling reaction. In the cross-coupling step, the nature of the ligands bound to the silicon atom is crucial to the efficiency of the reaction. Hence, the in situ formation of the cyclopropyltrifluorosilane via a ligand exchange with boron trifluoride etherate is required for good yields. The final chapter of this work is on the nickel-catalyzed cyclization of alkyl iodides via a homolytic aromatic substitution mechanism. A series of tetrahydronaphthalene and thiochroman related compounds have been synthesized using this methodology. A mechanistic study has confirmed the radical nature of this reaction and strongly suggests the catalytic role of nickel. DOSY NMR spectrometric investigations have demonstrated an association between substrate, the base employed in this reaction and the nickel complex.