Methyl-Substituted Dispiro-1,2,4,5-tetraoxanes: Correlations of Structural Studies with Antimalarial Activity

Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]- hexadecanes) 3 and 4 were designed as metabolically stable analogues of the dimethylsubstituted dispiro-1,2,4,5-tetraoxane prototype WR 148999 (2). For a positive control we selected the sterically unhindered tetraoxane 5 (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecane), devoid of any substituents. Tetraoxanes 3 and 4 were completely inactive in contrast to tetraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes possess sufficient steric hindrance about the tetraoxane ring due to the two additional axial methyl groups to prevent their activation to presumed parasiticidal carbon radicals by inhibiting electron transfer from heme or other iron(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both spirocyclohexyl rings are in a chair conformation and the bond lengths and angles are all quite normal except for the C1-C2 bond which is slightly lengthened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 reveals that molecular mechanics (MMX and MM3) and 3-21G* calculations each gave accurate structural parameters such as bond lengths, bond angles, and dihedral angles. In contrast, semiempirical methods such as AM1 gave poor results

Influence of Succinimide Dispersants on Film Formation, Friction and Antiwear Properties of Zinc Dialkyl Dithiophosphate

ZDDP (zinc dialkyldithiophosphate) is arguably the most successful antiwear additive ever employed in crankcase engine lubricants. It was originally used as an antioxidant and shortly afterwards recognized for its antiwear and extreme pressure properties. Unfortunately, another critical additive polyisobutylsuccinimide-polyamine (PIBSA-PAM), which is used as a dispersant in engine oils, is known to be antagonistic to ZDDP in terms of film formation, friction and wear. The mechanisms of this antagonism have been widely studied, but they are still not well understood. Furthermore, in order to protect engine exhaust catalysts from sulphated ash, phosphorus and sulphur (SAPS) and extend drain intervals of engine lubricants, a progressive reduction in ZDDP quantity but a growth in the use of PIBSA-PAM is required. The aim of this study is to explore the mechanisms and practical effects of the antagonism between ZDDP and PIBSA-PAM. Of particular interest is the impact on performance of the ratio of ZDDP to PIBSA-PAM, as measured by P:N ratio. Since ZDDP is a very effective antiwear additive, it produces only very low or "mild" rates of wear. To study this requires a new way to measure mild wear behaviour of formulated oils. Several techniques have been applied in this study to investigate the film formation, friction and wear properties of ZDDP- and/or PIBSA-PAM-containing oils. These include a new mild wear testing method, which is tested and developed using a range of different types of additives. It is found that the ratio of P:N plays a strong role in determining tribofilm formation and friction of ZDDP/PIBSA-PAM blends. However it plays a much weaker role in determining wear behaviour. It is found that some PIBSA-PAMs have considerable friction-reducing properties in their own right. The results suggest that PIBSA-PAM may interfere with the behaviour of ZDDP in several ways: by forming a ZDDP/ PIBSA-PAM complex at the metal surfaces to reduce the local activity of ZDDP; by PIBSA-PAM partially removing the ZDDP film; possibly also by PIBSA-PAM blocking ZDDP from metal surfaces. The newly-developed wear testing method can be used conveniently and effectively to study mild wear properties not just of ZDDP but of a wide range of other additives

Studies of the thermal rearrangements of dispiro-1,2,4-Trioxanes

A series of α-alkoxy-3,6-dispiro-1,2,4-trioxanes have been synthesised by acid-catalysed perhydrolyses of α-alkoxy methylenecyclohexane oxides (provides ring A) to give selectively the corresponding 1-hydroperoxy-1-(hydroxymethyl)cyclohexanes followed by acid-catalysed condensation with an appropriate cycloalkanone (provides ring C). Analogous perhydrolyses catalysed by MoO2(acac)2 afforded mixtures of regioisomeric β-hydroxy hydroperoxides, albeit in overall increased yields. The resulting 1- (hydroperoxymethyl)-1-hydroxycyclohexanes allowed entry to the isomeric 3,5-dispiro- 1,2,4-trioxanes. X-ray crystallographic analysis of the isomeric dispiro-1,2,4-trioxanes revealed that (a) they originate from different diastereoisomers of the epoxide substrates, and (b) the 1,2,4-trioxane rings of the 3,5-isomers adopt distorted half-chair rather than chair conformations as a consequence of intramolecular 1,3-diaxial steric interactions. Modelling studies of the perhydrolysis process are in broad agreement with the regioselectivity of the acid-catalysed reactions, but suggest that the α-alkoxysubstituted epoxides can act as bidentate ligands which can adopt different binding modes to the Mo catalyst and hence provide alternative reaction pathways. Thermolysis of dilute solutions of the α-alkoxy-3,6-dispiro-1,2,4-trioxanes in decane afforded a variety of 13-, 14-, 15- and 20-membered fully ring-expanded keto lactones in high yield via stepwise, β-scission/radical recombination reactions in contrast to the partially ring-expanded oxalactones obtained previously from other 3,6-dispiro-1,2,4- trioxane derivatives. An investigation of substituent effects on the thermal rearrangement mechanisms of 3,6- dispiro-1,2,4-trioxanes using DFT calculations indicated that, after the initial O-O bond homolysis to form the corresponding oxy biradical, ring C generally opens significantly faster than the unsubstituted ring A because of the greater delocalisation of radical character into ring C. In these cases, the lowest rearrangement energy barrier links directly to the partially ring-expanded oxalactone product as observed experimentally. Methyl or methoxy substituents at the α-position of ring A render its ring opening by β- scission increasingly more competitive to that of ring C due to increased delocalisation of radical character onto the α-substituent, consistent with the ‘α-effect’. Methoxysubstituents are also noted to engage in close range interactions with the 1,2,4-trioxane ring. Since the energy barrier for ring A opening falls below that of ring C in the methoxy model, formation of the fully ring-expanded keto lactone becomes favoured.Engineering and Physical Sciences Research Council (EPSRC

Experimental and Theoretical Study of the Polynuclear Bismuth Compounds : Dimers, Clusters, Molecular Self-Assemblies and Polyhedral Cage Molecules

In the framework of this thesis, the polynuclear bismuth chemistry has been investigated from different perspectives with the main focus on four types of the chemical bonding. Thus, the section of bismuth–bismuth bonding affects redox/metathesis reactions of BiBr3 with bulky lithium silanide Li(thf)3SiPh2tBu in three different ratios, leading to the formation of a Bi–Bi bonded compound, (tBuPh2Si)4Bi2 as one of the reaction products. The quantum chemical study has been mainly performed to shed light on the processes of oligomerisation of R2Bi radicals and bismuth dimers. That is a major challenge in the context of ''thermochromicity'' and ''closed-shell interactions'' in inorganic chemistry of organobismuth compounds with homonuclear Bi–Bi bonds. The section of bismuth–transition-metal bonding gives a deep insight into the structures, the chemical bonding and the electronic behavior of heteronuclear bulky Bi–Fe cage-like clusters, cubic [Bi4Fe8(CO)28]4– and seven-vertex [Bi4Fe3(CO)9], on the experimental and theoretical level. The section of bonding in bismuth–cyclopentadienyl compounds represents a detailed theoretical and experimental study of molecular systems based on cyclopentadienyl bismuth units such as (C5R5)Bi2+, [(C5R5)Bi]n and (C5R5)BiX2 (R = H, Me; X = F, Cl, Br, I; n = 1-4) in order to develop an effective adjustment of their electronic and bonding behavior and then, to be able to manipulate highly fluxional Bi–C5R5 bonds. The experimental part of this section emphasizes the theoretical results by observation of the unprecedented nanoscopic supramolecular architecture [{(C5Me5)5Bi5Br9}{(CH2Cl2)(BiBr4)}]2, cationic molecule [(C5Me5)5Bi6Cl12]+ and zig-zag polymer chains [(C5Me5)BiX2] (X = Br, I). The section of icosahedral and macroicosahedral bismuthanediide oligomers is a conceptual approach to understand the structures and the electronic properties of highly symmetric molecules such as [RnBinM2n–4]4– (n = 12, 32, …) on the theoretical level. The obtained results open the way to their endohedral chemistry. To sum up, unique structural and bonding features of the molecular assemblies based on C5Me5-substituted bismuth halides, as well as the observed Bi−arene pi-complexations and inverted sandwich behavior found in the crystal cell of a Bi–Fe cluster, are an important step in the development of supramolecular chemistry and crystal engineering of the compounds of the heavy group 15 elements. Furthermore, the bismuth cage and cluster chemistry has taken one step forward. The largest cluster of the bismuth–iron family (Bi4Fe8) and the spherical aromaticity of seven-vertex Bi4Fe3 structure have been observed. The new examples of a Bi4 tetrahedron, stabilized by transition-metal groups, as well as bismuth’s square pyramidal (Bi5) nido-polyhedron-like and octahedral (Bi6) deltahedron-like cages, stabilized by C5Me5 and halo ligands, have been discovered. A new chapter in the theoretical chemistry of highly symmetric bismuth cage molecules (Bi12, Bi32) has been opened

X-Ray Structure Analysis and Topological Charge Density Studies of Gossypol Derivatives

Gossypol and gossypol derivatives are natural byproducts of a variety of cotton plant species that poses interesting chemical, biological, and medicinal properties that are currently heavily researched. Supporting evidence suggest that gossypol and gossypol derivatives act on the Bcl-2 proteins that have been linked to certain cancers. Gossypol amine derivatives, specifically, are actively researched and a variety of amine derivatives have already been synthesized. However, gossypol and its derivatives are challenging compounds to work with because many of its derivatives tend to exist in various tautomeric forms. When analyzing gossypol and its derivatives it is the complex electron configuration that dictates the chemical mechanism and biological activity. The following research provides a charge density study that describes in detail the electronic configuration via Bader\u27s topological analysis of di(methoxy)gossypol and di(propylamino) gossypol. In addition, a series of crystallographic studies of gossypol amine derivatives and di(methoxy)gossypol are also analyzed

X-Ray Structure Analysis and Topological Charge Density Studies of Gossypol Derivatives

Gossypol and gossypol derivatives are natural byproducts of a variety of cotton plant species that poses interesting chemical, biological, and medicinal properties that are currently heavily researched. Supporting evidence suggest that gossypol and gossypol derivatives act on the Bcl-2 proteins that have been linked to certain cancers. Gossypol amine derivatives, specifically, are actively researched and a variety of amine derivatives have already been synthesized. However, gossypol and its derivatives are challenging compounds to work with because many of its derivatives tend to exist in various tautomeric forms. When analyzing gossypol and its derivatives it is the complex electron configuration that dictates the chemical mechanism and biological activity. The following research provides a charge density study that describes in detail the electronic configuration via Bader\u27s topological analysis of di(methoxy)gossypol and di(propylamino) gossypol. In addition, a series of crystallographic studies of gossypol amine derivatives and di(methoxy)gossypol are also analyzed

Design, Synthesis and Study of Redox and Optoelectronic Properties of Aromatic Oxidants and Polycyclic Aromatic Hydrocarbons

Organic materials play a significant role for the next generation photovoltaic devices that convert solar energy into usable forms of energy. In this regard, polycyclic aromatic hydrocarbons (PAHs) are fundamental tools in the developing area of molecular electronics and photovoltaics as they show excellent optical/electronic properties and are well-suited for applications in such developing areas as flexible display devices, field effect transistors and solar cell panels. Design and synthesis of novel materials for photovoltaics applications would require the proper understanding the mechanism of charge transport and identification of the structural features necessary in a particular molecular wire or PAH. To understand the charge transport mechanism and the hole delocalization one needs to generate the cation radical of a given electron donor in solution by using robust aromatic oxidants. Among these oxidants, magic blue has been widely used as an aromatic oxidant for the one electron oxidation due to its commercial availability and a reasonable oxidizing power. However, a modest stability of the magic blue salt leads to a slow decomposition to produce unknown impurities, which have been named “blues brothers”. Importantly, these impurities produce a noticeable band in the near-IR region—that is the same region where one usually expects to see an intervalence band of the cation radical with extensive hole delocalization. In this work a rational approach to synthesis of novel analogue of the magic blue that does not undergo degradation has been demonstrated. Furthermore, in the course of the rational design of novel molecular wires with enhanced redox and optical properties, one usually considers various geometrical factors in order to control the mechanism of charge delocalization. For example, a relatively small interplanar dihedral angle between adjacent units in poly-p-phenylene wire leads to a significant interchromophoric electronic coupling and thereby to extensive hole delocalization. However, it remains unclear how change in the interplanar angle would impact the redox and optical properties of the wire as well the mechanism of the hole delocalization in its cation radical. Accordingly, in this work it has been described the syntheses and study of the electrochemical and optoelectronic properties of a number of different series of biaryls connected by different numbers of methylene group to vary the dihedral angle in order to probe the mechanism and extent of hole delocalization in biaryls. Although significant progress has been made in understanding the charge transport mechanisms in various polycyclic aromatic hydrocarbons (PAHs), the usefulness of such materials in functional devices remains limited; hence design and synthesis of new PAHs to better understand the charge transport mechanisms remains an active area of research. An oxidative cyclodehydrogenation strategy was used for synthesizing a highly soluble, fluorene based larger derivative of hexa-peri-hexabenzocoronene (FHBC), where twelve carbon-carbon bonds are formed in a single step. Deployment of fluorenes at the periphery of the HBC core not only imparts solubility to the structure, but also allows the new PAHs to be functionalized further to make bigger PAHs to tune its desirable electronic properties

Regio- and stereoselectivity of the Norrish-Yang photocyclization of dialkyl 1,2- diketones. Solution versus solid state photochemistry of two polymorphs

As shown by X-ray crystallography, crystals of 3-acetoxy-16,17-seco17,20-dioxopregn-5-ene-16-nitrile are dimorphic. The regioselectivity of the Norrish-Yang type II photocyclization under visible light of this steroidal 1,2-diketone which bears primary, secondary, and tertiary nonequivalent abstractable gamma-hydrogens, dramatically increases in the crystalline state of both polymorphs. X-Ray crystallography and molecular mechanics calculations reveal crystal structure-solid state photochemistry relationships