Thesis (Ph.D.) - University of St Andrews, November 2009.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1983. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.A.)--University of Wisconsin--Madison, 1967. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Quantitative studies of global radiation damage are presented for two different types of experiments in structural biology: macromolecular crystallography (MX) and small angle X-ray scattering (SAXS) MX is the most common technique to elucidate the atomic resolution structures of biological macromolecules. However, these molecules undergo radiation induced changes during the experiment that undesirably affect the data. Global radiation damage, which is characterised by an overall loss in the diffracted intensity of Bragg reflections, limits the amount of useful data that can be collected from a single crystal in an experiment. Furthermore, for experimental phasing experiments, the radiation induced intensity changes can be so significant that the phasing signal becomes undetectable, thereby hindering successful structure determination. This thesis investigates methods to track and correct the diffraction data that are affected as a result of global radiation damage. First, extensions to the diffraction weighted dose (DWD) metric are investigated for the ability of DWD to track the overall intensity decay of reflections. This metric then is combined with a new mathematical model of intensity decay to perform zero-dose extrapolation. An additional probabilistic extrapolation approach is incorporated into the traditional regression based approach to allow extrapolation of low multiplicity reflections. As an alternative approach, a new hidden Markov model representation of the data collection experiment is developed that allows the time-resolved calculation of structure factor amplitudes, with error estimates calculated explicitly. This method gives comparable refinement statistics to that obtained from data processed with the current data reduction pipeline, and improvements to the algorithm are proposed. SAXS, on the other hand, is a complementary structural technique that results in low resolution information about macromolecules. However it still requires the probing of the macromolecules with ionising radiation, so radiation induced changes are still a problem. Unfortunately the tools for assessing radiation damage in SAXS experiments are not mature enough for them to be used routinely. This thesis presents extensions to RADDOSE-3D to perform dose calculations for SAXS samples. Additionally, a free, open source Python library has been developed to allow the exploration and visualisation of the results of a similarity analysis of frames within a dataset. These tools are then used to determine the efficacy of various radioprotectant compounds at different concentrations to mitigate radiation damage effects.

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The crystal and molecular structure of perylene has been refined from new three-dimensional data, confirming the gross features of the structure previously determined from two projections. The positional and thermal parameters of the carbon atoms have been refined by least-squares and differential syntheses and the hydrogen atoms have been approximately located. There are small but significant deviations from a completely planar arrangement; seemingly a result of slight intermolecular steric effects. A comparison of the measured bond lengths with those predicted by the valence-bond and molecular-orbital theory shows fairly close agreement with both sets of figures; the peri-bond lengths are 1.471-0.005 Å. In a similar vein the molecular structure of pyrene was refined by least-squares and differential synthesis treatment of new three-dimensional data. The thermal motion of the atoms was found to be anisotropic and was interpreted in terms of rigid body vibrations. Small corrections were made to the bond lengths to correct errors due to rotational oscillations. The general variation of the mean bond distances is in agreement with trends predicted by valence-bond and molecular-orbital calculations, but the individual agreements are not very good. The molecule is slightly non-planar, probably as a result of crystal packing forces. Hydroformylation of tri-O-acetyl-D-glucal yields two isomeric products and, to establish the configurations, X-ray analysis of the p-bromobenzenesulphonyl derivative of one of these has been carried out. The bromine and sulphur positions were determined from the three-dimensional Patterson function and the other atoms were located from successive three-dimensional Fourier summations. Refinement was carried out by least-squares methods. The derivative studied is 1-0-(p-bromobenzenesulphonyl)-4,5,7-tri-0-acetyl-2, 6-anhydro-3-deoxy-b-glucoheptitol, and this establishes the configurations of the triacetyl derivatives and parent polyols. The sugar ring is in the chair position with all substituents equatorial. 10-Chloro-5,10-dihydrophenarsazine crystallizes from xylene with half a molecule of xylene of crystallization in a monoclinic space group. This material rapidly loses the solvent of crystallization, the solvent-free crystals being orthorhombic. The complete structure of the orthorhombic crystals has been determined using Patterson methods to determine the arsenic and chlorine positions and a three-dimensional electron-density distribution map to locate the other atoms. All the positional and anisotropic thermal parameters were refined by least-squares. The molecule is slightly folded about the As-N axis, the angle between the two o-phenylene groups being 169°, and the chlorine atom being outside this angle. The deviation from planarity is thus not very large and it is unlikely that geometrical isomers could be isolated. / Science, Faculty of / Chemistry, Department of / Graduate

The crystal structure of 1,5-diphenyltricyclo [2.1.0.0²˒⁵] pent-3-yl p-bromobenzoate has been determined by X-ray diffraction. The crystals are triclinic, a = 5.92, b = 8.98, c = 17.85 Å, ⍺ = 89°17', β = 82°46', Ɣ = 89°50', Z = 2, space group Pī. The structure was determined with visual Cu-K[formula omitted] data by heavy atom Patterson and Fourier methods, and the positional and thermal parameters were refined by least-squares, the final discrepancy index R, being 0.16 for 1228 observed reflections. The tricyclopentane system is highly strained, with six C-C-C angles of 60°, three of 80°, and four of 90°, and an intramolecular non-bonded C...C distance of 1.99 Å. The C-C bond lengths are similar to those of normal single bonds, except for the bond common to the two three-membered rings, which may possibly be slightly shorter than the others. / Science, Faculty of / Chemistry, Department of / Graduate

Single crystal X-ray diffraction methods have been used to investigate four organic compounds, two monosaccharide derivatives and two nitrobenzene compounds: 1. methyl 3-C-(carbomethoxymethyl)-4,6-di-O-p-chlorobenzoyl-2,3- dideoxy-α-D-ribo-hexopyranoside, C(24)+H(24)+C(12)O(8); 2. 5-0-(p-bromobenzenesulphonyl)-2,2'-O-cyclohexylidene-3-deoxy-2-C- hydroxymethyl-D-erythro-pentono-1,4-lactone, C(18)H(21)BrO(7)S; 3. 2,6-dichloro-4-nitroaniline, C(6)H(4)Cl(2)N(2)O(2); 4. ethyl 3,5-dinitrobenzoate, C(6)H(8)N(2)O(6). Crystals of the di-(p-chlorobenzoate) derivative of a novel branched-chain sugar, methyl 3-C-(carbomethoxymethyl)-2,3-dideoxy-α-D-ribo-hexopyranoside, are monoclinic, space group, P2(1), a = 5•752, b = 15•436, c = 13•698 Ǻ., Β = 93•74° and Z = 2. Intensity data have been measured on an automatic diffractometer, firstly with Mo-K(α) radiation, then more accurately with Cu-K(α) radiation. Efforts to confirm the molecular structure of the derivative have been unsuccessful, although various methods of analysis have been employed; the principal approaches have been the examination of the Patterson and sharpened Patterson maps, and by direct methods, the application of the tangent formula in the phase determination procedures for noncentrosymmetric space groups. None of the methods has produced any encouraging, distinctive portions of the molecule, and at present, the investigation has been halted. The structure of "a"-D-isosaccharinic acid has been determined by crystal structure analysis of a derivative which was shown to be 5-0-(p-bromo-benzenesulphonyl)-2,2'-0-cyclohexylidene-3-deoxy-2-C-hydroxymethyl-D-erythro-pentono-l,4-lactone. Crystals are monoclinic, a = 5•757, β = 10•586, c = 16•021 Ǻ., 8 = 98•85°, Z = 2, space group P2(1). The intensities of 1319 reflections were measured with a scintillation counter and Cu-K(α) radiation, the structure was derived from Patterson and electron-density maps, and refined by least-squares methods, the final R being 0•10 for 1140 observed reflections. The absolute configuration is established, since the compound was obtained by degradation of cellulose. Each of the two five-membered rings in the derivative has an envelope conformation, with one atom displaced from the plane of the other four .In the 1,3-dioxolane ring, the displacement is 0•49 Ǻ.; the γ-lactone ring is less prominently bent, with displacement only 0•14 Ǻ. The bond distances and valency angles in the molecule do not differ significantly from the usual values, and the intermolecular distances correspond to van der Waals' interactions. Crystals of 2,6-dichloro-4-nitroaniline are generally twinned; they are monoclinic, space group P2(1)/c, a = 3•723, b = 17•833, c = 11•834 Ǻ., 8 = 94•12°, Z = 4. Intensity data were collected for one of the twins on an automatic diffractometer. The coordinates of the two chlorine atoms were found in a Patterson map and all the other atoms in electron-density and difference Fourier maps. The structure was refined by full-matrix least-squares methods to R = 0•038. There are only slight deviations from overall planarity of the molecule, the amino and nitro groups being rotated by 6•3 and 7•2° respectively out of coplanarity with the benzene ring. The amino group appears to be held nearly coplanar with the benzene ring by intermolecular N-H...0 and intramolecular N-H...C1 / Science, Faculty of / Chemistry, Department of / Graduate

In contrast to 1,1'-binaphthyl, racemic 4,4'-dimethyl-1,1'-binaphthyl does not undergo spontaneous resolution upon heating from room temperature to just below the melting point. Optically active dimethyl binaphthyl may be obtained by seeding the racemic melt site optically active naphthidine. The crystal structures of both the racemic and optically active dimethyl binaphthyls were solved in the hope of understanding the above observations. The racemate crystallizes in the monoclinic space group C2/c with cell parameters a=13.225, b=10.768, c= 11.572 Å and β=114.040. There are four molecules per unit-cell; two have the B and two have the S configuration. The structure was solved using direct methods and refined to R=0.074. There is a 3° head in the plane of the naphthalene residues, which are cis-oriented with an angle of 68° between them. The optically active form belongs to one of the tetragonal space groups P4₁2₁2 or P4₃2₁2 with cell parameters a = b = 8.3031 and c = 23.706 Å. Direct methods sere used to solve the structure and the final R was 0.060. There are four molecules per unit-cell of identical configuration, but it could not be determined whether this was R or S. The naphthalene residues show a 2.7° bend and are also cis-oriented, but with an angle of 80° between them. Bond lengths and angles are consistent with values previously reported for 1,1'-binaphthyl and naphthalene. The racemate packs somewhat more efficiently and perhaps for this reason it is slightly more stable than the optically active form- It is difficult however to explain the difference in behaviour between the methylated and unmethylated binaphthyls on the basis of these results alone. Further studies would include the crystal structures of optically active 1,1'-binaphthyl and various naphthidines. / Science, Faculty of / Chemistry, Department of / Graduate