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acase@tulane.edu / Since the mid-20th century supramolecular chemistry has become a thriving field in synthetic chemistry. Supramolecular assemblies are assemblies of molecules formed and stabilized by non-covalent interactions. Deep-cavity cavitands, bowl-shaped molecules, are one such class of molecules that form assemblies using the hydrophobic effect when in the presence of suitable hydrophobic guests in an aqueous environment. Computer simulations allow us to study these assemblies at the molecular level and provide valuable insight into both the thermodynamics of assembly as well as provide information relevant to the design of the next generation of deep-cavity cavitands. This research begins by investigating dimeric capsules of a deep-cavity cavitand known as Octa-acid (OA). We use Molecular Dynamics to study a homologous series of n-alkane guests in order to learn some of the "rules" of guest packing. Additionally we use a machine learning technique to harvest a dominant conformation from each simulation and compare computed chemical shifts of that structure with experimental chemical shifts. The second part of this dissertation looks into multimeric systems formed by one of OA's derivatives known as Tetra-endomethyl Octa-acid (TEMOA). The entrance to the binding pocket of TEMOA is narrower than OA due to four methyls being added to its rim. TEMOA forms not only dimers, but also tetramers and hexamers, depending on the guest size. We use free energy techniques to show that guest packing primarily drives the transitions between each assembly state. Additionally we obtain the interior volumes of each multimer and demonstrate that they now approach that of structures formed by other means. We give insight into why TEMOA forms multimeric systems and OA does not. The last section of this dissertation compares the interior hydration characteristics of OA and TEMOA. We show that the small structural changes from OA to TEMOA promote a large change in wetting/dewetting behavior inside the binding pocket. Normally OA is full of water in its interior, but TEMOA exhibits a two-phase behavior. Here we also demonstrate a simple bridge between simulation and experiment to validate our findings by using partial molar volume calculations. / 1 / James Wesley Barnett

Functionalizing the upper rim of resorcinarene-based cavitands allows a variety of compounds to be synthesized from a single scaffold. Using the upper-rim moieties as ligands for a variety of transition metal ions further increases the versatility of this class of host compounds. A new resorcinarene-based molecule functionalized with four pyridine and acetic acid ligands has been successfully prepared to explore the properties of metal-assembled complexes. To synthesize this compound, tetra(bromomethyl)cavitand was reacted with N-(2-pyridylmethyl)-N-ethylacetate amine to give ethyl acetate pyridine resorcinarene. Hydrolysis of the ester gave acetic acid pyridine resorcinarene (APRes) in good yield. Complexes with Cu2+, Co2+, and Zn2+ are currently being investigated and characterized by MS and 1H and 13C NMR.

Doctor of Philosophy / Department of Chemistry / Stefan Kraft / In the present study, the rescorcin[4]arenes decorated with an alternating arrangement of pyridinium and sulfonate moieties were synthesized to establish a molecular quadrupole. These rescorcin[4]arenes are capable of undergoing conformational changes from a ‘collapsed’ to ‘open’ state. The stability of the two state are controlled by the polarity of the solvent environment. The electrostatic interactions between pyridinium and sulfonates enforced a ‘quadrupolar collapse’ in solvents such as chloroform. While these interactions are disrupted in dimethylsulfoxide. A major synthetic challenge was functionalizing the resorcin[4]arene in a positive/negative/positve/negative pattern was successfully addressed. Comparison to dipolar resorcin[4]arene were undertaken to establish a quantitative measurement of the quadrupolar forces and to address the question of cooperatively provided addition attraction beyond two dipoles. A,C-functionalized-bis sulfonate resorcin[4]arenes and A,C function bis-pyridinium resocin[4]arenes were synthesized independently. Combining these dicationic and dianionic moieties provided an interdigitating dimeric unit with overall quadrupolar charge distribution. Disruption of the quadrupolar salt bridges in CDCl[subscript]3 was accomplished through the addition of DMSO or through dilution. DeltaG[superscript]o, DeltaH[superscript]o, and DeltaS[superscript]o have been determined for the dimer formation. Addition of pyridinium salts led to a disruption of the dimeric capsule. Host-guest binding studies established attractive binding to CS[superscript]2. Larger guests such as toluene, diiodobenzene, dicynanobenzene could not be encapsulated.

Cyclodextrins (CDs) are cyclic oligosaccharides of various sizes containing several α-(1→4)-linked D-(+)- glucopyranose units. The commercially available ones comprise six, seven or eight glucose units, named respectively α-CD, β-CD and γ-CD. Their truncated cone-like and well-defined cavity are particularly attractive for the encapsulation of a variety of substrates. As such, they found numerous applications in many areas of chemistry. A recent development, from which the present work is inspired, consisted in covalently linking transition metals to CD cavities in order to perform and study catalytic reactions in a confined environment featuring steric repulsive or attractive noncovalent interactions with the substrate or/and the metal coordination sphere.The first part of this thesis focuses on reviewing transition metal-based cavitands, for which the first and second metal coordination spheres are controlled by their cavity-shaped ligand. The following chapters are concerned with the synthesis, coordination and catalytic properties of two new phosphane ligands built on a large β-CD scaffold. The first one, named WIDEPHOS, is a diphosphine having two phenylphosphinidene "PPh" units capping adjacent glucose units on a methylated β-CD. This ligand features two phosphorus lone pairs pointing to the cavity interior but not aligned. These geometrical features, combined with the large distance separating the two phosphorus atoms, promote the formation of "imperfect" trans-chelate complexes in which the metal centre swings about the ligand. This unprecedented molecular movement, christened "oschelation", allows each phosphorus atom to form an optimal bond in turn with the coordinated d8 and d10 transition metal ions. Further studies on WIDEPHOS proved that it is better suited for coordinating dinuclear fragments within the confinement of the large β-CD cavity. Severe steric constrains on the metal first sphere of coordination result in the formation of single μ-chlorido bridged dinuclear species. In this new type of square planar complexes, non-optimal orbital overlapping measured by the so-called tilt angle was also found to take place for one of the phosphorus atom together with an "oschelation" movement involving non identical donor atoms, namely a phosphorus and an oxygen atom. Static gold(I) dinuclear complexes displaying similar imperfect orbital overlapping for one of the phosphorus atom were also prepared.

Les cyclodextrines (CDs) sont des oligosaccharides cycliques constituées de monomères D-(+)-glucopyranose liés entre eux par des liaisons glycosidiques α-(1→4). Les plus utilisées sont celles qui comportent six, sept ou huit unités glucose, et sont appelées α-CD, β-CD et γ-CD, respectivement. Grâce à leur structure "cage", les cyclodextrines sont capables de former des complexes d'inclusion avec diverses molécules, ouvrant ainsi la voie à des applications dans de nombreux domaines de la chimie. Un des développements les plus récents, à l’origine des travaux présentés dans cette thèse, concerne l'élaboration de molécules associant de manière covalente une cyclodextrine et un métal de transition,composés particulièrement adaptés à l'étude de réactions catalytiques confinées et/ou fonctionnant en mode supramoléculaire.La première partie de ce mémoire est une mise au point donnant un aperçu du rôle croissant joué en chimie des métaux de transition par des ligands hybrides associant des centres donneurs et une entité cavitale.Les chapitres suivants sont consacrés à la synthèse de deux ligands phosphorés originaux construits sur une plateforme β-CD, ainsi qu’à l’étude de leurs propriétés complexantes et catalytiques. Le premier, WIDEPHOS, est une β-CD méthylée qui intègre deux unités phenylphosphinidène "PPh" pontant chacune deux unités glucose adjacentes. Dans cette diphosphine qui est conçue comme un chélateur à très grand angle de chélation, les doublets libres des atomes de phosphore pointent vers l’intérieur de la plateforme CD. En présence d'entités MX2 "carré-plan" (M = Pd, Pt,Rh), WIDEPHOS forme des complexes chélate caractérisés par un angle P-M-P proche de 160º, autrement dit conduit à des complexes de stéréochimie trans "imparfaite". Cette dernière est à l’origine d'un mouvement de balancier du ligand autour du métal, l’oschélation, un mouvement qui permet à chacun des atomes de phosphore d’optimiser, à tour de rôle, la liaison qu’il forme avec le métal complexé. Une autre propriété remarquable de WIDEPHOS concerne sa propension à former des espèces dinucléaires dans lesquelles les deux centres métalliques sont confinés dans l’espace cavital. Les contraintes induites par la formation de tels complexes sont manifestes au niveau de l’angle d’inclinaison τ de l’un des atomes de phosphore ainsi que par l’apparition d’un mouvement d’ "oschélation" d’un fragment P,O constitutif de la CD. / Cyclodextrins (CDs) are cyclic oligosaccharides of various sizes containing several α-(1→4)-linked D-(+)- glucopyranose units. The commercially available ones comprise six, seven or eight glucose units, named respectively α-CD, β-CD and γ-CD. Their truncated cone-like and well-defined cavity are particularly attractive for the encapsulation of a variety of substrates. As such, they found numerous applications in many areas of chemistry. A recent development, from which the present work is inspired, consisted in covalently linking transition metals to CD cavities in order to perform and study catalytic reactions in a confined environment featuring steric repulsive or attractive noncovalent interactions with the substrate or/and the metal coordination sphere.The first part of this thesis focuses on reviewing transition metal-based cavitands, for which the first and second metal coordination spheres are controlled by their cavity-shaped ligand. The following chapters are concerned with the synthesis, coordination and catalytic properties of two new phosphane ligands built on a large β-CD scaffold. The first one, named WIDEPHOS, is a diphosphine having two phenylphosphinidene "PPh" units capping adjacent glucose units on a methylated β-CD. This ligand features two phosphorus lone pairs pointing to the cavity interior but not aligned. These geometrical features, combined with the large distance separating the two phosphorus atoms, promote the formation of "imperfect" trans-chelate complexes in which the metal centre swings about the ligand. This unprecedented molecular movement, christened "oschelation", allows each phosphorus atom to form an optimal bond in turn with the coordinated d8 and d10 transition metal ions. Further studies on WIDEPHOS proved that it is better suited for coordinating dinuclear fragments within the confinement of the large β-CD cavity. Severe steric constrains on the metal first sphere of coordination result in the formation of single μ-chlorido bridged dinuclear species. In this new type of square planar complexes, non-optimal orbital overlapping measured by the so-called tilt angle was also found to take place for one of the phosphorus atom together with an "oschelation" movement involving non identical donor atoms, namely a phosphorus and an oxygen atom. Static gold(I) dinuclear complexes displaying similar imperfect orbital overlapping for one of the phosphorus atom were also prepared.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / A family of bis-pyridine based pharmaceutical active ingredients were synthesized and co-crystallized with four iodoperfluoroalkanes. Thirteen new crystal structures that are driven by I‧‧‧N(py) halogen bonds, are presented and compared with that of their hydrogen-bonded analogues. Halogen bonded co-crystals exhibit two different structural arrangements, as opposed to layered architectures observed in hydrogen bonded co-crystals. In order to explore the effect of aromatic stacking interactions on hydrogen and halogen bond driven co-crystallization process, we utilized a series of aromatic hydrogen and halogen bond donors in combination with bis-pyridine based pharmaceutical active ingredients. Aromatic stacking between the donor and the acceptor were limited, due to the lack of complementarity between the donor and the acceptor in terms of size, shape and geometry. In that case, homomeric interactions between the single components were translated into the structure of the binary co-crystals. According to our charge calculations, similarly activated hydrogen and iodine atoms possess similar electrostatics. Therefore, we wanted to investigate the interchangeability of hydrogen bonds and halogen bonds by utilizing 2-aminopyrimidine as the backbone for C(sp)-H and C(sp)-I functionalities which makes self-complementary ribbons via NH‧‧‧N synthons. Our results show that the ethynyl proton is capable of acting as a synthon mimic of ethynyl iodine by interchangeable C(sp)-H‧‧‧N hydrogen bonds and C(sp)-I‧‧‧N halogen bonds. We exploited the halogen bonding donor capability of iodo, bromo and chloro ethynyl functionalities towards a series of halide ions. Based on the grinding experiments these donors showed 90%, 70% and 50% success rates towards halides. Among the halides, chlorides exhibited the highest red shift compared to bromides and iodides. We synthesized a series of cavitands functionalized with hydrogen bond donor and acceptor groups and studied their binding preferences towards a series of active ingredients. We have shown that suitably functionalized cavitands can act as carriers of active ingredients and especially, selective binding of aspirin is demonstrated using a two-point binding mode.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / Supramolecular synthesis relies upon the creative and rational use of the common intermolecular forces and a proper understanding of these forces is critical for design and assembly of molecular building blocks into extended networks. The strength of seven substituted pyridines as hydrogen-bond acceptors was probed using a series of fifteen mono/dicarboxylic acids to demonstrate the interrelationship between the charge on the substrate and its ability to form co-crystals/salts. The higher charge in the acceptor led to proton transfer (100% yield) from the hydrogen bond donor to give a salt, whereas the lower charge led to co-crystals. This specificity observed for small molecules was extended to an investigation of selectivity in ditopic molecules. A series of nineteen hydrogen-bond donors, including fifteen carboxylic acids and four cyanoximes, were tested for binding preferences against ten ditopic ligands with variable charges. The overall supramolecular yield of 82% (9/11) proved a high degree of reliability in terms of best acceptor/donor approach, hence establishing the efficiency of the calculated charges as a guideline for molecular recognition processes. Solubility and thermal properties of pharmaceutical drug mimics were altered via formation of co-crystals/salts. The ligands and their co-crystals/salts with five even-chain dicarboxylic acids were synthesized and their comparative solubility in pure water and in pH 6.8 buffer solution measured. Solubility enhancement to a degree of 9x is observed for pharmaceutical drug haloperidol, whereas decrease in solubility down to 81% is achieved for 2-amino-5-(3-pyridyl)pyrimidine (which has agrochemical significance). Also the thermal and solubility behavior of these co-crystals were shown to reflect the properties of their parent co-crystallizing agents, allowing for a modulation of physical properties. Finally, the specificity and selectivity of the intermolecular interactions observed for small molecules were applied in the synthesis of hydrogen and halogen-bonded capsules. Several resorcinarene-based cavitands were synthesized and their upper rim decorated with acetamidopyridyl, aminopyrazinyl, 3-pyridyl, and 4-pyridyl moieties with hydrogen and halogen-bonding potentials. A homomeric hydrogen-bonded capsule was formed with self-assembly of acetamidoethynylcavitand via N-H···O=C interactions, whereas a heteromeric halogen-bonded capsule, the very first of its kind, was formed with N···I halogen-bonded interaction between 3-pyridylcavitand and tetrafluoroiodo-substituted calixarene.

Ce mémoire est consacré à la synthèse et à l'étude de coordinats phosphorés originaux construits sur des résorcinarènes rigidifiés. Trois types de ligands ont été élaborés : 1) des phosphines tertiaires obtenues par ancrage de groupes –PPh2 sur des cycles aromatiques d'un résorcinarène générique. Celles-ci réagissent avec des espèces cationiques en formant des complexes chélate P,O résultant du clivage d'une liaison C–O localisée en ortho du cycle phosphoré. Ce type de cassure, inédit, permet d'accéder à des catalyseurs d'oligomérisation d'éthylène pour la production de chaînes courtes; 2) des diiminophosphoranes obtenus par fonctionnalisation distale d'un résorcinarène-cavitand. Un ligand de cette famille donne lieu à des sélectivités de forme en hydrogénation (Rh) de mélanges d'oléfines; 3) des phosphino-cavitands doubles permettant d’engendrer, par chélation, des métallo-capsules. L'une d'entre elles (Pt) conduit à des sélectivités remarquables en hydroformylation du styrène. / This thesis describes the synthesis of three types of phosphorus-containing resorcinarene cavitand: a) compounds with diphenylphosphino groups grafted to the wider rim of a generic cavity. These phosphines undergo facile, directed C–O bond breaking upon reaction with transition metal ions in the presence of exogenous or endogenous nucleophiles. A nickel complex of this type was shown suitable for the low pressure production of short α-olefins starting from ethylene; b) cavitands distally-substituted by two iminophosphoranyl groups (–Ph2P=NAr). One of them (Ar = p-anisyl), when combined with Rh(I), resulted in a shape-selective olefin hydrogenation catalyst; 3) double phosphino-cavitands, which upon chelation gave metallo-capsular complexes in which the metal centre is either fully or partially embedded in the resulting cavity. A platinum complex of this type resulted in the selective hydroformylation of styrene into the expected branched aldehyde.