Structure of Molecules and Assemblies

A broad overview is presented about the importance of molecular structure determination and about the structural considerations that come in view when molecular units build assemblies. Structural chemistry and crystallography constitute an integral part of today\u27s supramolecular chemistry as demonstrated by various statements of giants of the field. The challenge of supramolecular chemistry to the structural chemist is in detecting and understanding the structural changes accompanyingmolecular recognition and assembly formation and in providing assistance for the design of new assemblies and molecular devices with desired properties

Structure of Molecules and Assemblies

A broad overview is presented about the importance of molecular structure determination and about the structural considerations that come in view when molecular units build assemblies. Structural chemistry and crystallography constitute an integral part of today\u27s supramolecular chemistry as demonstrated by various statements of giants of the field. The challenge of supramolecular chemistry to the structural chemist is in detecting and understanding the structural changes accompanyingmolecular recognition and assembly formation and in providing assistance for the design of new assemblies and molecular devices with desired properties

Dynamic Studies of Excited-state Proton Transfer to solvent from Phenol and Its Derivatives in Water

学位記番号：工博乙9

Testing Electrostatic Complementarity in Enzyme Catalysis: Hydrogen Bonding in the Ketosteroid Isomerase Oxyanion Hole

A longstanding proposal in enzymology is that enzymes are electrostatically and geometrically complementary to the transition states of the reactions they catalyze and that this complementarity contributes to catalysis. Experimental evaluation of this contribution, however, has been difficult. We have systematically dissected the potential contribution to catalysis from electrostatic complementarity in ketosteroid isomerase. Phenolates, analogs of the transition state and reaction intermediate, bind and accept two hydrogen bonds in an active site oxyanion hole. The binding of substituted phenolates of constant molecular shape but increasing p K (a) models the charge accumulation in the oxyanion hole during the enzymatic reaction. As charge localization increases, the NMR chemical shifts of protons involved in oxyanion hole hydrogen bonds increase by 0.50–0.76 ppm/p K (a) unit, suggesting a bond shortening of ˜0.02 Å/p K (a) unit. Nevertheless, there is little change in binding affinity across a series of substituted phenolates (ΔΔG = −0.2 kcal/mol/p K (a) unit). The small effect of increased charge localization on affinity occurs despite the shortening of the hydrogen bonds and a large favorable change in binding enthalpy (ΔΔH = −2.0 kcal/mol/p K (a) unit). This shallow dependence of binding affinity suggests that electrostatic complementarity in the oxyanion hole makes at most a modest contribution to catalysis of ˜300-fold. We propose that geometrical complementarity between the oxyanion hole hydrogen-bond donors and the transition state oxyanion provides a significant catalytic contribution, and suggest that KSI, like other enzymes, achieves its catalytic prowess through a combination of modest contributions from several mechanisms rather than from a single dominant contribution

Topics in Phosphorus-Fluorine Chemistry

The reactions between primary amines and phosphorus penta- fluoride were complex and yielded alkylammonium hexafiuorophosphates, RNH+3 PF6- (R = Me, Et, But), and bis(alkylamino)trifluorophos- phoranes, (RNH)2PF3 (R = Me, Et, But). In addition a 2:1 adduct, 2MeNH2. PF5, was formed in the reaction with methylamine whereas 1:1 adducts, RNH2. PF5 (R = Et, But), were produced with ethyl-amine and t-butylamine. The preparation of alkylaminotetrafluoro-phosphoranes, RNHPF4 (R = Et, But), by the thermal decomposition of the 1:1 adducts was studied. Methylaminotetrafluorophosphorane could be prepared by the reaction between raethylaminotrimethyl-silane, Me3SiNHMe, and phosphorus pentafluoride. The formation of diazafluorodiphosphetidines from alkylamino-fluorophosphoranes was studied. Phosphorus pentafluoride and phenyltetrafluorophosphorane reacted with (MeNH)2PF3 to give (F3PNMe)2 and PhF(F2PNMe)2 respectively, but the yield of these products was low. The reaction between primary amines and phosphorus trifluoride proceeded by a two step process. Alkylaminodifluorophosphines, RNHPF2 (R = Me, Et, But, Bun), were formed in the initial step. The nature of the subsequent step is believed to depend on the steric properties of the attacking amine. Bis(alkylamino)difluoro-phosphoranes, (RNH)2PF2H (R = Me, Et, Bun), were usually isolated, but the bulky t-butylamine produced bis(t-butylamino)fluoro-phosphine, (But NH)2PF The compounds isolated above were characterised by their n.m.r., i.r. and mass spectra. Several fragmentation modes for molecules of the type RNHP(F) are discussed. Infra-red correlations for the RNH-P group are also made. The bulk of the evidence suggests that the extra molecule of amine in 2MeNH2. PF5 is co-ordinated to the 1:1 adduct by means of N---H hydrogen-bonding. Several routes to produce PNP bridges were investigated. Difluorophosphino(tetrafluorophosphoranyl)methylamine, PF2NMePF4, was best prepared from the reaction between phosphorus penta- fluoride and difluorophosphino(trimethylsilyl)methylamine, Me3SiNMePF2, which was itself prepared from the reaction between heptamethyldisilazane and chlorodifluorophosphine. A similar reaction between POF3 and Me3SiNMePF2 only gave low yields of difluorophosphino(difluorophosphoryl)methylamine, PF2NMePOF2. The latter was more conveniently synthesized from chlorodifluoro phosphine and methylaminophosphoryl difluoride, MeNHPOF2. The ease of reaction between Me3SiNMeX (X = P(F), SiMe3) and a phosphorus-fluoride could be correlated with the Lewis basicity of the former and the Lewis acidity of the latter. The spectroscopic properties of the bridged compounds produced were examined. Attempts to prepare PNS bridges by the above routes failed, and possible reasons for this are discussed. The products isolated from the reaction of SOF2 with either MeNHPF2 or Me3SiNMePF2 included methylaminothiophosphoryl difluoride, MeNHPSF2, and MeNHPOF2, which were fully characterised. The addition of HPSF2 to alkenes took place at room temperature under the influence of U.V. light to give alkylphosphonothioic difluorides, RPSF2 (R = Et, Prn, Bun), which were fully characterised. Evidence is presented which suggests that the ease of the U.V. induced addition of a phosphorus-halide to an alkene depends on the strength of the P-X (X = F, Cl, Br) bonds in the latter compound. It proved possible to isolate and characterise 2-bromoethylphosphonic difluoride, BrC2H4POF2, from the reaction between ethylene and bromophosphoryl difluoride

The prediction of mutagenicity and pKa for pharmaceutically relevant compounds using 'quantum chemical topology' descriptors

Quantum Chemical Topology (QCT) descriptors, calculated from ab initio wave functions, have been utilised to model pKa and mutagenicity for data sets of pharmaceutically relevant compounds. The pKa of a compound is a pivotal property in both life science and chemistry since the propensity of a compound to donate or accept a proton is fundamental to understanding chemical and biological processes. The prediction of mutagenicity, specifically as determined by the Ames test, is important to aid medicinal chemists select compounds avoiding this potential pitfall in drug design. Carbocyclic and heterocyclic aromatic amines were chosen because this compounds class is synthetically very useful but also prone to positive outcomes in the battery of genotoxicity assays.The importance of pKa and genotoxic characteristics cannot be overestimated in drug design, where the multivariate optimisations of properties that influence the Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) profiles now features very early on in the drug discovery process.Models were constructed using carboxylic acids in conjunction with the Quantum Topological Molecular Similarity (QTMS) method. The models produced Root Mean Square Error of Prediction (RMSEP) values of less than 0.5 pKa units and compared favourably to other pKa prediction methods. The ortho-substituted benzoic acids had the largest RMSEP which was significantly improved by splitting the compounds into high-correlation subsets. For these subsets, single-term equations containing one ab initio bond length were able to accurately predict pKa. The pKa prediction equations were extended to phenols and anilines.Quantitative Structure Activity Relationship (QSAR) models of acceptable quality were built based on literature data to predict the mutagenic potency (LogMP) of carbo- and heterocyclic aromatic amines using QTMS. However, these models failed to predict Ames test values for compounds screened at GSK. Contradictory internal and external data for several compounds motivated us to determine the fidelity of the Ames test for this compound class. The systematic investigation involved recrystallisation to purify compounds, analytical methods to measure the purity and finally comparative Ames testing. Unexpectedly, the Ames test results were very reproducible when 14 representative repurified molecules were tested as the freebase and the hydrochloride salt in two different solvents (water and DMSO). This work formed the basis for the analysis of Ames data at GSK and a systematic Ames testing programme for aromatic amines. So far, an unprecedentedly large list of 400 compounds has been made available to guide medicinal chemists. We constructed a model for the subset of 100 meta-/para-substituted anilines that could predict 70% of the Ames classifications. The experimental values of several of the model outliers appeared questionable after closer inspection and three of these have been retested so far. The retests lead to the reclassification of two of them and thereby to improved model accuracy of 78%. This demonstrates the power of the iterative process of model building, critical analysis of experimental data, retesting outliers and rebuilding the model.EThOS - Electronic Theses Online ServiceEPSRCGlaxoSmithKlineGBUnited Kingdo

Design of Redox-active Ligands: In Pursuit of Stable Radicals, their Complexes, and Assembly of Paramagnetic Coordination Clusters.

This thesis describes the design, synthesis, properties, and coordination chemistry of redoxactive ligands. This thesis also explores new ways of expanding our ligand systems, in order to improve their binding capacities. We accomplished this by utilizing familiar redox-active moieties and structures to those published previously in our group, but with enhanced topological capacities and predictable structural outcomes. Chapter 1 begins with a general outline of the fundamental principles that govern organic radicals including; their reactivity, their properties and applications, and how these can be applied to the design of ligands for polynuclear assembly. Chapter 2 starts with a brief overview of arylazo ligands and the synthesis of a new hydrazone substituted phenalenol ligand (2.1). In the following section (2.2) we use this ligand to produce homoleptic ligand mixed-valence complexes featuring trivalent cobalt and iron metals. The chapter is concluded (2.3) with the synthesis of a new ditopic aryl-azo ligand and its cobalt coordination chemistry involving a neutral tetra-radical/tetra-nuclear molecular grid featuring valence tautomerism. Chapter 3 begins with the design and synthesis of a new ditopic diamino phenol ligand, which was found to oxidize to a neutral stable phenoxyl radical (3.1-3.2). The solution properties, which include reversible pi-dimerization of this stable radical are also described (3.3), and later the substitution chemistry of this new ligand is explored (3.4). In chapter 4, we describe the coordination chemistry of this new ditopic aminophenol ligand, which includes assembly into several coordination clusters involving copper (4.2), iron (4.3), nickel (4.4), and zinc (4.5). These coordination clusters feature the ligand in a variety of oxidation states; including rare examples of dianion “aminyl” radical clusters. In chapter 5, we begin with a description of a new synthetic derivative which can be used for the construction of larger tetratopic or asymmetric diamino phenol ligands. In 5.2 we describe the synthesis of a tetratopic aminophenol ligand along with its reactivity and aerial oxidation to a tri-phenoxyl radical. In 5.3, we conclude the thesis with the use of an asymmetric diamino phenol ligand and it’s Cu(II/III) coordination chemistry, which displayed unique reactivity with molecular oxygen

New Intermediates from Photogenerated Phenyl Cations

La tesi presenta uno studio sulla fotoreattività di composti aromatici volta ad ampliare la classe di substrati in grado di fotogenerare alfa,n-dideidrotolueni a partire da aril cationi nel loro stato di tripletto. Viene riportato inoltre lo studio fotochimico di arilazo mesilati come nuovi prescursori di aril cationi e radicali. In aggiunta viene presentato un approccio fotocatalitico per la generazione di intermedi reattivi svoltosi presso l’Università di Ratisbona. Il lavoro è corredato dallo studio computazionale e meccanicistico sulle reazioni fotochimiche studiate sperimentalmente.This thesis is devoted to the study of the aromatic compounds photoreactivity and in particular to widen the number of alfa,n didehydrotoluenes precursors from photogenerated triplet aryl cations. The photochemical investigation on arylazo mesylates photoreactivity as novel aryl radicals and cations generators is also presented. Moreover, all reactions experimentally studied are analysed on the basis of computational chemistry