Coordination and Organometallic Chemistry of Novel Gallium Complexes: Synthesis, Reactivity and Spectroscopy

The work described in this thesis incorporates three main themes: the synthesis and reactivity of new coordination and organometallic gallium compounds, and the chemical state determination of molecular gallium complexes using XPS and XAS. The coordination chemistry of low valent gallium cations was explored using macrocyclic ethers as ligands. The experimental oxidation number, or chemical state, of newly synthesized low valent gallium cationic complexes was compared to known compounds to allow for the assessment of the electronic environment at gallium. The organometallic chemistry of gallium was examined using donor ligands to stabilize monomeric organogallium(III) compounds, demonstrating the ability to substitute the ligands on gallium and to generate a compound containing a gallium-carbon double bond. Two multinuclear low valent gallium cations were synthesized using cryptand[2.2.2] as a stabilizing ligand and Ga2Cl4(THF)2 as a starting material. Conventional characterization techniques and computational methods were used to examine the structure and bonding of the cationic gallium cores contained within the cryptand ligand. These compounds are the first examples of binuclear cryptand[2.2.2] complexes, where two metal centres are located within the cryptand cavity. The experimental chemical states, namely the experimentally determined electronic environments or partial charges, of the gallium centres in two gallium-cryptand[2.2.2] complexes were evaluated using X-ray photoelectron spectroscopy (XPS) and X-ray absorption spectroscopy (XAS) as a means of probing the electronic environment of the gallium centres. The experimental XPS data of the gallium-cryptand complexes were compared to known gallium compounds with unambiguously assigned oxidation numbers to determine the electron density at the gallium centres and to allow for an assessment of their potential reactivity. To overcome the instrumental limitations of the XPS experiments, XAS studies of the synthesized gallium-cryptand[2.2.2] complexes and other low valent gallium compounds with multiple gallium atoms were performed to separate the signals originating from the individual gallium centres. The higher resolution of the XAS data allowed for the observation of multiple signals from gallium centres with different assigned oxidation numbers within a single complex and gave additional information on the electronic structure and bonding of the cryptand complexes in conjunction with computational studies. The synthesis and reactivity of a gallium(I) cationic complex using 12-crown-4 as a stabilizing ligand was explored. The synthesis of [Ga(12-crown-4)][GaCl4] was achieved in one step from commercially available starting materials. Anion exchange reactions to replace the reactive tetrachlorogallate anion for the perfluorophenylborate were performed. [Ga(12- crown-4)][B(C6F5)4] was analyzed using XPS, which allowed for the classification of the gallium(I)-crown ether complex as electron deficient. Reactions of the gallium(I)-crown ether complex with Cp*K, cryptand[2.2.2], and DMAP demonstrated the facile synthesis of known gallium(I) compounds as well as the generation of novel gallium(I) cations, highlighting the use of the gallium(I)-crown ether complex as an effective starting material for new gallium(I) compounds. The synthesis of a compound with a gallium-carbon double bond, a gallene, was explored. The synthetic route utilized was inspired by strategies reported for the synthesis of compounds containing main group element-carbon double bonds with the key step being a dehydrohalogenation of a gallium(III) fluoride. The precursor organogallium(III) fluorides were synthesized using an NHC and DMAP as donors ligands to stabilize neutral species. Dehydrohalogenation of the gallium(III) fluoride was examined in an attempt to generate a gallene. Tolualdehyde was used as a trapping agent in situ, resulting in the formation of a 2:1 cycloadduct, giving evidence for the generation of an intermediate gallene. The synthetic route presented highlights the use of donor stabilization to facilitate ligand substitution and exchange reactions for neutral organogallium compounds

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Chemical state determination of molecular gallium compounds using XPS

A series of molecular gallium compounds were analyzed using X-ray photoelectron spectroscopy (XPS). Specifically, the Ga 2p and Ga 3d photoelectron binding energies and the Ga L M M Auger electron kinetic energies of compounds with gallium in a range of assigned oxidation numbers and with different stabilizing ligands were measured. Auger parameters were calculated and used to generate multiple chemical speciation (or Wagner) plots that were subsequently used to characterize the novel gallium-cryptand[2.2.2] complexes 1-3 that possess ambiguous oxidation numbers for gallium. The results presented demonstrate the ability of widely accessible XPS instruments to experimentally determine the chemical state of gallium centers and, as a consequence, provide deeper insights into reactivity compared to assigned oxidation and valence numbers. 3/2 5/2 3 45 4

Synthesis and Characterization of Cationic Low-Valent Gallium Complexes of Cryptand[2.2.2]

The synthesis and characterization of two bimetallic, cationic low-valent gallium-cryptand[2.2.2] complexes is reported. The reaction of cryptand[2.2.2] with Ga2Cl4 gave two different cations, [Ga3Cl4(crypt-222)]+ (1) or [Ga2Cl2(crypt-222)]2+ (2), depending on whether or not trimethylsilyl triflate (Me3SiOTf) was added as a co-reagent. Complexes 1 and 2 are the first examples of bimetallic cryptand[2.2.2] complexes, as well as the first low-valent gallium-cryptand[2.2.2] complexes. Computational methods were used to evaluate the bonding in the gallium cores

(tert-Butyl isocyanide-κC)trichloridogallium(III)

The crystal structure of (tert-butyl isocyanide-κC)trichloridogallium(III), [GaCl3(C5H9N)], features the first reported isocyanide–gallium trihalide complex. The Ga—C—N—C fragment is essentially linear. The methyl fragments of the tert-butyl group are eclipsed with the chloride ligands on the Ga atom. The molecule does not, however, exhibit threefold crystallographic symmetry, as it crystallizes within the P21/c space group

Reactivity of sulfonyl-containing compounds with ditetrelenes

The addition of a variety of sulfones and a sulfoxide to ditetrelenes (a disilene and a digermene) was examined. The reaction of benzenesulfonyl chloride with tetramesityldisilene or tetramesityldigermene results in the formation of the 1,2-addition products, 2-chlorotetramesityldisilyl- or digermylbenzenesulfinate. The addition of p-toluenesulfonyl chloride to the disilene gave the analogous product, 2-chlorotetramesityldisilyl p-toluenesulfinate. In contrast, benzenesulfonyl fluoride, diphenyl and dimethyl sulfone did not react with either the disilene or the digermene. The unprecedented formation of the sulfinates reveals a selective 2-electron reduction of the sulfur centres using ditetrelenes. The addition reactions of sulfonyl compounds illustrates the potential of ditetrelenes to serve as reducing agents which react rapidly, at room temperature under mild conditions. The reaction of tetramesityldisilene with diphenyl sulfoxide resulted in the formation of tetramesityloxadisilirane and with benzene sulfonic acid resulted in the formation of 1,1,2,2-tetramesityldisilyl benzenesulfonate

The Diverse Reactivity of Disilenes Toward Isocyanides

The addition of 2,6-dimethylphenyl isocyanide and t-butyl isocyanide to tetramesityldisilene was examined. In both cases, the initially formed product is an iminodisilirane; however, the iminodisiliranes are unstable under the reaction conditions and react with a second equivalent of the isocyanide to give either a 3-silaazetidine or a novel bicyclic double enamine, respectively. Taken together with the previous examples in the literature, the results demonstrate that subtle differences in the steric bulk of the disilene or the electronic effects of the isocyanide can lead to dramatic differences in the reaction pathway

The Addition of a Cyclopropyl Alkyne to an Asymmetrically-Substituted Disilene: A Mechanistic Study

The addition of (2-ethynyl-3-methoxy-2-methylcyclopropyl)benzene to Tip Si=SiTipPh, a disilene with an asymmetric substitution pattern, was investigated. The regiochemistry of the ring-opened products indicates a stepwise mechanism with a biradical intermediate. The results are consistent with those obtained in similar experiments with symmetrically substituted disilenes.

Synthesis and Reactivity of Novel Boranes Derived from Bulky Salicylaldimines: The Molecular Structure of a Maltolato Compound

Reductive amination of salicylaldehyde or 3,5-di-tert-butylsalicylaldehyde and 1-adamantylamine using NaBH4 gave the corresponding aminoalcohols in high yields. Subsequent addition of one equivalent of H3B·SMe2 to the aminoalcohols, with loss of two equivalents of dihydrogen, resulted in the formation of adamantanyl oxazaborinanes (1a,b). The molecular structure of 1b was studied by a single crystal X-ray diffraction study. Crystals were obtained from a saturated Et2O solution and belong to the triclinic space group Pī with unit cell parameters a = 9.1267(4) Å; b = 11.676(2) Å; c = 12.240(3) Å; α = 66.840(3)°; β = 78.529(3)°; and γ = 67.354(3)°. The molecular structure of the addition product (2a) arising from maltol and 1a was also confirmed by single crystal X-ray diffraction. Crystals were obtained from a saturated 1:2 mixture of toluene/Et2O and belong to the orthorhombic space group Pna2(1) with unit cell parameters a = 18.519(6) Å; b = 17.315(5) Å; and c = 12.680(4) Å. The asymmetric unit contains two molecules that differ slightly in some of the dihedral angles