京都大学 / 新制・課程博士 / 博士(工学) / 甲第23927号 / 工博第5014号 / 新制||工||1783(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 松田 建児, 教授 杉野目 道紀, 教授 生越 友樹 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Quantum mechanical methods are becoming increasingly useful and applicable tools to complement and support experiment. Nonetheless, some barriers to further applications of theoretical models still remain. A coupled cluster singles and doubles (CCSD) calculation, a reliable ab initio method, scales approximately on the order of 𝑂(𝑁⁶), where 𝑁 is a measure of the system size. This unfortunately limits the use of such high-accuracy methods to relatively small systems. Coupled cluster property calculations must be used in conjunction with reduced-scaling methods in order to broaden the range of applications to larger systems. In this work, we introduce some of the underlying theory behind such calculations and test the performance of several local correlation techniques for polarizabilities, optical rotations, and excited state properties. In general, when the computational cost is significantly reduced, the necessary accuracy is lost. Polarizabilities are less sensitive to the truncation schemes than optical rotations, and the excitation data is often only in agreement with the canonical result for the first few excited states. Additionally, we present a novel application of equation-of-motion coupled cluster singles and doubles to simulated circularly polarized luminescence spectra of eight chiral ketones. Both the absorption in the ground state and emission from the excited states were examined. Extensive geometry analyses were performed, revealing that optimized structures at the density functional theory were adequate for the calculation accurate coupled cluster excitation data. / Ph. D.

Au cours de ce travail de doctorat, nous avons d'abord étudié un aspect fondamental de la chiralité au niveau moléculaire visant à observer des différences d'énergie entre deux énantiomères provenant d'effets de violation de la parité (PV). Nous avons en particulier examiné les complexes oxorhénium chiraux dont les deux énantiomères présentent théoriquement des énergies d'absorption infrarouge différentes. Leur propriétés chiroptiques, en particulier leur dichroïsme circulaire vibrationnel (VCD), ont été examinées. D'autres complexes métalliques chiraux comme des complexes de platine portant un carbone asymétrique fluoré ont été préparés. Par ailleurs, nous avons étudié la chiralité hélicoïdale provenant de la fusion en ortho de plusieurs cycles aromatiques. Ainsi, des hélicènes portant des fonctionnalités bi-pyridines ont été synthétisés et ont montré des propriétés photophysiques et chiroptiques intéressantes. La présence d'unité chélatantes de type N^N’ ou N-C nous a permis d'étudier l'influence de la coordination de divers métaux de transition (Re(I) et Pt(II)) sur les propriétés et de concevoir de nouveaux commutateurs chiroptiques acido-basiques. / In this PhD work, we first investigated a fundamental aspect of chirality at the molecular level aiming to determine the parity violation (PV) energy difference between two enantiomers. We focused on chiral oxorhenium complexes for which the two corresponding enantiomers show theoretically different infrared absorption energies. Their chiroptical properties and especially their vibrational circular dichroism (VCD) were examined. Other chiral metal complexes such as platinum complexes bearing an asymmetric fluorinated carbon have also been prepared. Furthermore, we have investigated the helical chirality derived from the skew shape of ortho-fused aromatic ring. Indeed, helicenes bearing 2,2’-bipyridine functionalities were synthesized and they showed interesting photophysical and chiroptical properties. The presence of N^N’ or N-C chelating moieties enabled us to study the coordination effect of different transition metals (Re(I) and Pt(II)) on their properties and to conceive new acid-base triggered chiroptical switches.

Les cryptophanes constituent une famille de conteneurs moléculaires, caractérisés par leur cavité interne lipophile. La capacité des cryptophanes à encapsuler du xénon hyperpolarisé a ouvert une grande opportunité de développer des traceurs d’IRM moléculaires à base de 129-Xe. Un grand nombre de biocapteurs 129-Xe-cryptophane ont été développés pour cibler divers événements biologiques. Bien que ce concept soit accrocheur, de nombreux défis ont été rencontrés, en particulier dans l’élaboration de dérivés de cryptophane solubles dans l’eau et fonctionnalisables facilement. Cette thèse vise donc à développer une nouvelle approche simple pour synthétiser des capteurs de cryptophane solubles dans l’eau. Ces cages sont basées sur des dérivés de cryptophane [223] portant une fonction acide carboxylique centrale permettant de greffer de manière sélective une unité de détection et sur six précurseurs solubles dans l’eau sur les deux rebords du CTB. Le greffage de différents bras de détection a été réalisé en une seule étape, suivie d’une simple déprotection pour offrir les capteurs de cryptophane solubles dans l’eau. Ces capteurs ont été caractérisés par spectroscopie RMN 129-Xe pour évaluer leurs propriétés de liaison et leur réactivité. Un autre aspect de ces dérivés est leur capacité à subir un phénomène d’self-encapsulation dépendant de solvants, caractérisé par l’inclusion de la fonctionnalité centrale greffée sur le lieur propélendioxy vers la cavité interne des cryptophanes en l’absence d’invité. L’investigation de «l’auto-encapsulation» a été évaluée par spectroscopie RMN 1H et IR qui a révélé certains signaux caractéristiques correspondant à ce processus. L'effet sur les propriétés chiroptiques globales a également été étudié par spectroscopie polarimétrique, VCD et ECD. / Cryptophanes are a family of molecular containers, characterized by their lipophilic internal cavity. The ability of cryptophanes to encapsulate hyperpolarized xenon has opened a great opportunity to develop highly sensitive 129-Xe-based MRI molecular tracers. A large number of 129-Xe-cryptophane biosensors have been developed for targeting various biological events. Although this concept is catchy, many challenges have been encountered, specifically in the elaboration of water soluble and easy functionalizable cryptophane derivatives. The work presented in this thesis aims at developing a new straightforward approach to synthesize water soluble cryptophane sensors. These cages are based on cryptophane-[223] derivatives that bear a central carboxylic acid function to selectively graft a sensing unit, and six water soluble precursors on the cryptophanes’ rims. Using these platforms, three different water soluble sensors have been elaborated. These sensors have been characterized by 129Xe NMR spectroscopy to assess their binding properties and responsiveness. An additional aspect of these derivatives is their ability to undergo a solvent-dependent “self-encapsulation” phenomenon. This is characterized by the inclusion of the central functionality grafted on the propelendioxy linker towards the inner cavity of cryptophanes. This phenomenon has been clearly proved by 1H NMR and IR spectroscopy. The effect on the overall chiroptical properties was also investigated by polarimetry, VCD and ECD spectroscopy.

Mes travaux de thèse se sont portés sur la synthèse d'hélicènes organométalliques et hétéroatomiques, et se divisent suivant trois axes majeurs. Le premier sujet est l'étude des hélicènes avec un centre métallique redox. Nous avons introduit un motif chimique contenant un atome de fer sur l'hélicène connecté par une liaison C≡C. Dans ce sujet, nous avons étudié les propriétés chiroptiques avec le changement d'état redox du centre métallique. Pour cela, nous avons utilisé des techniques spectroscopiques chiroptiques comme le dichroïsme circulaire vibrationnel, le spectre d'activité optique Raman qui opèrent dans la région infrarouge. Le deuxième sujet est l'étude d'hélicènes avec un centre rédox et un centre photochrome. Nous avons introduit l'hélicène sur un bloc chimique contenant du ruthénium connecté par liaison une C≡C, puis introduit le motif photochrome DTE (dithiényléthène) sur le ruthénium. La molécule contient donc trois parties : un centre chiral, un centre rédox et un centre photochrome. Dans ce sujet, nous avons étudié l'activité d'interrupteur chiroptique provoquée par un stimulus redox et/ou par la lumière. Le troisième sujet est l'étude de platinahélicènes et de borahélicènes qui sont issus de l'incorporation d'un ou deux platinacycles ou cycles azaboroles dans le squelette de l'hélicène. Dans ce sujet, nous avons examiné les propriétés optiques et chiroptiques, et étudié l'influence du nombre de cycles et du nombre d'hétérocycles. Ces produits ont également révélé des propriétés d'émission et de la luminescence polarisée circulairement. / My PhD work has focused on the synthesis of organometallic and heteroatomic helicenes and is separated into three subjects. The first subject is the study of helicene with one redox metal center. We have introduced a building block containing an iron atom on the helicene connected by a C≡C bond. In this subject, we have studied the chiroptical properties with the change of the redox state of the metal center. Besides, we have used the techniques of chiroptical spectroscopies such as the vibrational circular dichroism, the Raman optical activity which occur in the infrared region. The second subject is the study of helicenes with one redox center and one photochromic center. We have introduced the helicene on the ruthenium building block, and then introduced a photochromic unit DTE (dithienylethene) on the ruthenium through C≡C bonds. This molecule contains three parts: one chiral center, one redox center and one photochromic center. In this subject, we have studied the redox- and/or light-triggered chiroptical switching activity. The third subject is the study on the platinahelicenes and borahelicenes which show one or two platinacycles or azaborole cycles incorporated in the helicene skeleton. In this subject, we have studied the optical and chiroptical properties, and also studied the influence of the number of cycles and number of the heterocycles. These compounds are also studied in the emission properties and circularly polarized luminescence.

In quantum chemistry, scientists aim to solve the time-independent Schrödinger equation by employing a variety of approximation techniques whose accuracy are typically inversely proportional to their computational cost. This problem is amplified when it comes to chiral molecules, whose stereochemical assignments and associated chiroptical properties can be incredibly sensitive to small changes in their three-dimensional structure, requiring highly accurate theoretical methods. On the other hand, due to the polynomial scaling with system size, it is sometimes impractical to apply such methods to chemical compounds of broad scientific interest, especially when a multitude of low-energy conformations have to be accounted for as well. As a result, the assignment of absolute configurations to chiral compounds remains a tedious task. However, the characterization of these compounds is something that many different scientists are significantly invested in. The ultimate goal, then, is twofold: to gain useful insight by utilizing the electronic structure methods at your disposal while simultaneously developing new approximation techniques that can be used to push the boundaries on what is currently capable in computational chemistry. Therefore, we start by applying widely accepted density functional theory methods to predict optical rotations and electronic circular dichroism for naturally occurring antiplasmodial and anticancer drug candidates. We find that by comparing the computational results directly with those obtained through experimental measurement, we can provide reliable absolute config- uraitonal assignments to a variety of chiral compounds with numerous stereogenic centers. We also present the first ever prediction of vibrational circular dichroism with second-order Møller-Plesset perturbation theory. This extension opens the door to systematically improvable correlated wave function methods that can be employed when density functional theory fails or when higher accuracy results are required. / Doctor of Philosophy / Theoretical chemistry aims to draw a line from a molecule's three-dimensional structure to a set of physical observables, allowing for the efficient prediction of such properties. One family of chemical compounds for which this task becomes increasingly difficult is known as chiral molecules. A chiral compound is defined as one that has a non-superimposable mirror image. The concept of chirality is most tangibly seen with a pair of human hands, which demonstrate this same mirror-like behavior. In the same way that a person has left and right hands, a three-dimensonal handedness can be used to characterize many compounds that are essential to life including enzymes, sugars, and proteins. Although procedures have been developed to consistently isolate pure samples of such compounds, the correct identification of each hand poses a much larger task and costs the global pharmaceutical industry tens to hundreds of millions of dollars every year. As such, gaining insight about these incredibly valuable compounds and their associated properties is a never ending goal for many scientists. One such way to gain insight is through the direct comparison of experimental and calculated properties, namely chiroptical properties. These unique properties define how chiral compounds interact with light. While experimental scientists are limited in the degree to which they can probe a molecule's structure, theoretical chemists have the advantage of knowing the exact three-dimensional structure for the compound they are studying. On the other hand, theoretical chemists rely on comparison to experimental results to develop new methods or apply the available techniques to predict molecular properties. This work begins by attempting to match calculated properties to experimentally measured ones in order to confirm the detailed molecular structure of natural product drug candidates. Through multiple such computational studies, it is shown that the current methods are sometimes limited in the knowledge that they can provide. As a result, it is absolutely necessary to continue to improve on the existing methods. We go on to provide a first-of-its-kind implementation that allows for theoretical chemists to compare their results to experiment in a way that was not previously possible.

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The precision synthesis of helical bilayer nanographenes (NGs) with new topology is of substantial interest because of their exotic physicochemical properties. However, helical bilayer NGs bearing non-hexagonal rings remain synthetically challenging. Here we present the efficient synthesis of the first helical bilayer nonbenzenoid nanographene (HBNG1) from a tailor-made azulene-embedded precursor, which contains a novel [10]helicene backbone with two embedded heptagons. Single-crystal X-ray analysis reveals its highly twisted bilayer geometry with a record small interlayer distance of 3.2 Å among the reported helical bilayer NGs. Notably, the close interlayer distance between the two layers offers intramolecular through-space conjugation as revealed by in situ spectroelectrochemistry studies together with DFT simulations. Furthermore, the chiroptical properties of the P/M enantiomers of HBNG1 are also evaluated by circular dichroism and circularly polarized luminescence.