Investigations on the use of amidic ligands in copper-catalysed arylation reactions

This thesis reports investigations on the use of amidic ligands, in particular picolinamide ligands, in copper-catalysed arylation of nucleophiles with aryl halides. An introduction to the field of copper-catalysed arylations of nucleophiles, mostly focusing on the mechanistic aspects of these processes, from the early investigations to the most recent developments, is reported in Chapter 1. Following this introduction, the results of this research are presented in three chapters, each dealing with a different topic. Chapter 2 reports on the synthesis of a range of differently substituted picolinamide ligands and their use in the copper-catalysed arylation of phenols and amides. The catalytic screenings reported in this chapter are the basis for the mechanistic investigations reported in Chapter 4. A range of phenols, amides and aryl halides were tested under optimised conditions to assess the validity of the method. All the coupling products were isolated and characterised. Chapter 3 describes the synthesis of copper complexes with picolinamide ligands, to be used for mechanistic investigations. Five different types of complexes, with differently substituted ligands, were obtained, and their structural features in the solid state are summarised in this chapter. Discussion on the mechanism of formation of these complexes, and on the role of the base in the process is also included. Investigations on the mechanism of the coupling reaction between phenols and aryl halides, facilitated by picolinamide ligands, are reported in Chapter 4. The complexes synthesised in Chapter 3, used as pre-catalysts for the coupling process, and electrochemical measurements on these complexes, are employed to investigate the role of the electronic properties of the ligands in the reaction, and its influence on the metal centre. Other miscellaneous experiments, such as radical clock experiments, are also reported. The final two chapters of this thesis, Chapters 5 and 6, contain general conclusions and suggestions for further investigation topics (Chapter 5), and detailed experimental procedures and characterisation data for all of the compounds prepared in Chapters 2-4 (Chapter 6)

Rapid Liquid Chromatography-Tandem Mass Spectrometry Analysis of Two Urinary Oxidative Stress Biomarkers: 8-oxodG and 8-isoprostane.

Human biomonitoring of oxidative stress relies on urinary effect biomarkers such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and 8-iso-prostaglandin F2α (8-isoprostane); however, their levels reported for similar populations are inconsistent in the scientific literature. One of the reasons is the multitude of analytical methods with varying degrees of selectivity used to quantify these biomarkers. Single-analyte methods are often used, requiring multiple injections that increase both time and cost. We developed a rapid ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to quantify both urinary biomarkers simultaneously. A reversed-phase column using a gradient consisting of 0.1% acetic acid in water and 0.1% acetic acid in methanol/acetonitrile (70:30) was used for separation. The MS detection was by positive (8-oxodG) and negative (8-isoprostane) ion-mode by multiple reaction monitoring. Very low limit of detection (<20 pg/mL), excellent linearity (R2 > 0.999), accuracy (near 100%), and precision (CV < 10%) both for intra-day and inter-day experiments were achieved, as well as high recovery rates (>91%). Matrix effects were observed but were compensated by using internal standards. Our newly developed method is applicable for biomonitoring studies as well as large epidemiological studies investigating the effect of oxidative damage, as it requires only minimal clean up using solid phase extraction

Visible light-promoted iron-catalyzed C(sp2)-C(sp3) Kumada cross-coupling in flow

X.-J.W., I.A., J.A., and T.N. would like to acknowledge the European Union for a Marie Curie ITN Grant (Photo4Future, Grant No. 641861). C.S. acknowledges the European Union for a Marie Curie European post-doctoral fellowship (FlowAct, Grant No. 794072). We would like to thank the Engineering and Physical Sciences Research Council for financial support (EP/M02105X/1). C. L. thanks the Prof. & Mrs Purdie Bequests Scholarship and AstraZeneca for his PhD Studentship.A continuous‐flow, visible‐light‐promoted method has been developed to overcome the limitations of iron‐catalyzed Kumada–Corriu cross‐coupling reactions. A variety of strongly electron rich aryl chlorides, previously hardly reactive, could be efficiently coupled with aliphatic Grignard reagents at room temperature in high yields and within a few minutes’ residence time, considerably enhancing the applicability of this iron‐catalyzed reaction. The robustness of this protocol was demonstrated on a multigram scale, thus providing the potential for future pharmaceutical application.Publisher PDFPeer reviewe

Synthesis of different glutathione–sulfur mustard adducts of verified and potential biomarkers

Sulfur Mustard (SM) is a blistering agent used as a chemical weapon. Glutathione (GSH) is involved in the β-lyase degradation pathway of SM and recently, bioadducts between SM and GSH were observed in vitro. While these bioadducts have never been isolated from in vivo tests or real poisoning with SM, they could be of interest as potential future biomarkers for the retrospective validation of exposure. We herein report the synthesis of different observed and new potential GSH–SM bioadducts as reference materials for analytical investigation. Two distinct approaches were investigated: a building-block pathway and the direct reaction with GSH. The availability of these references will aid future studies and may lead to the discovery of new GSH–SM biomarkers

Unravelling the mechanism of cobalt-catalysed remote C-H nitration of 8-aminoquinolinamides and expansion of substrate scope towards 1-naphthylpicolinamide

Previously, an unexpected Co-catalysed remote C-H nitration of 8-aminoquinolinamide compounds was developed. This report provided a novel reactivity for Co and was assumed to proceed through the mechanistic pathway already known for analogous Cu-catalysed remote couplings of the same substrates. In order to shed light into this intriguing, and previously unobserved reactivity for Co, a thorough computational study has now been performed, which has allowed for a full understanding of the operative mechanism. This study demonstrates that the Co-catalysed remote coupling does not occur through the previously proposed Single Electron Transfer (SET) mechanism, but actually operates through a High-Spin Induced Remote Radical Coupling mechanism, through a key intermediate with significant proportion of spin density at the 5- and 7-positions of the aminoquinoline ring. Additionally, new experimental data provides expansion of the synthetic utility of the original nitration procedure towards 1-naphthylpicolinamide which unexpectedly appears to operate via a subtly different mechanism despite having a similar chelate environment

Effect of alkyl chain length on the properties of triphenylamine-based hole transport materials and their performance in perovskite solar cells

A new series of diacetylide-triphenylamine (DATPA) derivatives with five different alkyl chains in the para position, MeO, EtO, nPrO, iPrO and BuO, were synthesised, fully characterised and their function as hole-transport materials in perovskite solar cells (PSC) studied. Their thermal, optical and electrochemical properties were investigated along with their molecular packing and charge transport properties to analyse the influence of different alkyl chains in the solar cell parameters. The shorter alkyl chain facilitates more compact packing structures which enhanced the hole mobilities and reduced recombination. This work suggests that the molecule with the methoxy substituent (MeO) exhibits the best semiconductive properties with a power conversion efficiency of up to 5.63%, an open circuit voltage (Voc) of 0.83 V, a photocurrent density (Jsc) of 10.84 mA cm−2 and a fill factor of 62.3% in perovskite solar cells. Upon replacing the methoxy group with longer alkyl chain substituents without changing the energy levels, there is a decrease in the charge mobility as well as PCE (e.g. 3.29% for BuO-DATPA). The alkyl chain length of semiconductive molecules plays an important role in achieving high performance perovskite solar cells

Origins of High Catalyst Loading in Copper(I)-Catalysed Ullmann- Goldberg C-N Coupling Reactions

Mechanistic investigation of Ullmann-Golberg reactions using soluble and partially soluble bases led to identification of various pathways for catalyst deactivation through (i) product inhibition with amine products, (ii) byproduct inhibition with inorganic halide salts, and (iii) ligand exchange by soluble carboxylate bases. Reactions using a partially soluble inorganic bases showed variable induction periods, which is responsible for reproducibility issues in these reactons. Surprisingly, more finely milled Cs2CO3 resulted in longer induction period due to higher concentration of deprotonated amine/amide, leading to suppressed catalytic activity. These results have singificant implications on future ligand development for Ullmann-Goldberg reaction, and on the solid form of the inorganic bases as an important variable with mechanistic ramifications in many catalytic reactions

Origins of High Catalyst Loading in Copper(I)-Catalysed Ullmann- Goldberg C-N Coupling Reactions

Mechanistic investigation of Ullmann-Golberg reactions using soluble and partially soluble bases led to identification of various pathways for catalyst deactivation through (i) product inhibition with amine products, (ii) byproduct inhibition with inorganic halide salts, and (iii) ligand exchange by soluble carboxylate bases. Reactions using a partially soluble inorganic bases showed variable induction periods, which is responsible for reproducibility issues in these reactons. Surprisingly, more finely milled Cs2CO3 resulted in longer induction period due to higher concentration of deprotonated amine/amide, leading to suppressed catalytic activity. These results have singificant implications on future ligand development for Ullmann-Goldberg reaction, and on the solid form of the inorganic bases as an important variable with mechanistic ramifications in many catalytic reactions

Synthesis of marmycin A and investigation into its cellular activity

Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications