A quantitative scale for directing group power in ruthenium(II)-catalysed ortho-directed C-H arylation reactions

Previously held under moratorium from 19 October 2017 until 24 February 2022Directed ruthenium-catalysed C-H functionalisation of heteroarenes, such as 2-phenylpyridine or 1-phenylpyrazole, has emerged as an efficient and environmentally benign alternative to traditional cross-coupling chemistry. Using readily available and inexpensive aryl halides, the mechanisms of these transformations are beginning to be understood. However, there has been no work completed towards understanding the different directing group power of these substrates. Many of the literature examples consider only the behaviour of substrates with one functional group, and the behaviour of more densely functionalised substrates remains unpredictable. In this work we have presented a quantitative reactivity scale of directing group power for a series of ruthenium(II)-catalysed ortho-directed intermolecular C-H arylation reactions across a range of substrates. The scale of directing group power has been determined using sets of competition reactions that were analysed by calibrated GC-FID. Using least squares minimisation, relative reaction rates were obtained for each substrate delivering the first quantifiable assessment of directing group power. These results have found that, in our series, 2-phenylpyridine >> 2-phenylpyrazole > Nmethyl-2-phenyl-imidazole > 2-phenyloxazoline >> N-(1-phenylethylidene)aniline. These results cover a synthetically useful reactivity range of 10² and allow a quantitative prediction of site selectivity under the conditions examined. Additionally, we have presented initial experimental findings that support the intermolecular quantitative predictions within an intramolecular substrate. This sets the scene for prediction of regioselectivity in more densely functionalised molecules, on an inter- and intramolecular setting.Directed ruthenium-catalysed C-H functionalisation of heteroarenes, such as 2-phenylpyridine or 1-phenylpyrazole, has emerged as an efficient and environmentally benign alternative to traditional cross-coupling chemistry. Using readily available and inexpensive aryl halides, the mechanisms of these transformations are beginning to be understood. However, there has been no work completed towards understanding the different directing group power of these substrates. Many of the literature examples consider only the behaviour of substrates with one functional group, and the behaviour of more densely functionalised substrates remains unpredictable. In this work we have presented a quantitative reactivity scale of directing group power for a series of ruthenium(II)-catalysed ortho-directed intermolecular C-H arylation reactions across a range of substrates. The scale of directing group power has been determined using sets of competition reactions that were analysed by calibrated GC-FID. Using least squares minimisation, relative reaction rates were obtained for each substrate delivering the first quantifiable assessment of directing group power. These results have found that, in our series, 2-phenylpyridine >> 2-phenylpyrazole > Nmethyl-2-phenyl-imidazole > 2-phenyloxazoline >> N-(1-phenylethylidene)aniline. These results cover a synthetically useful reactivity range of 10² and allow a quantitative prediction of site selectivity under the conditions examined. Additionally, we have presented initial experimental findings that support the intermolecular quantitative predictions within an intramolecular substrate. This sets the scene for prediction of regioselectivity in more densely functionalised molecules, on an inter- and intramolecular setting

Monitoring and removal of natural organic matter (NOM) from Toowoomba water sources

Natural organic matter (NOM), present in all water sources, proves problematic for the water treatment industry due to its reaction with disinfectants, particularly chlorine. This reaction forms allegedly harmful, carcinogenic disinfection by-products. There are no regulatory limits in place in Australia for the quantifiable NOM surrogate parameter of organic carbon. Few studies have been conducted in Australia with the aim of quantifying the amount of NOM in water sources, with none having been conducted to investigate Toowoomba water sources. The aim of this dissertation was to investigate the amount of organic matter in certain water sources of Toowoomba, the removal of this by enhanced coagulation, and the trihalomethane formation potential of each of the water sources before and after treatment. The methodology used to achieve this involved the collection of water samples from four water sources, three of which are drinking water sources for the Toowoomba region treated by the Mt Kynoch Water Treatment Plant. The water sources include the Japanese Gardens, Cooby Dam, Perseverance and Cressbrook Dams, and a raw water mixture of the blended raw water sources collected immediately prior to treatment from the Mt Kynoch Water Treatment Plant. Water samples were collected weekly for a ten-week period for the purpose of measuring the pH, turbidity, conductivity, total dissolved solids, alkalinity, dissolved organic carbon, ultraviolet absorption, iron and certain anions. Additional water samples were collected to conduct jar tests to investigate the removal of the organic carbon by enhanced coagulation. The jar tests were performed with alum as the coagulant being added in 10 mg/L increments up to 100 mg/L. Trihalomethane formation potential testing was also carried out. In the absence of any Australian regulatory limits for organic carbon or treatment techniques, all experimental results for the Toowoomba water sources have been compared to the standards and practices in place in the United States. Experimental results revealed the average dissolved organic carbon concentrations to be 4.51 mg/L, 7.29 mg/L, 5.75 mg/L and 5.26 mg/L for the Japanese Gardens, Cooby Dam, Perseverance Dam and the Mt Kynoch mixture respectively. Each of these values is greater than 2.0 mg/L, used in the United States as the trigger for the implementation of further treatment. If the organic carbon concentration of a raw water source exceeds this value, further treatment in the form of enhanced coagulation must be implemented. Therefore, it is recommended that further treatment is necessary for these Toowoomba water sources to target the removal of the excessive organic carbon present, in accordance with the regulations in place in the United States. Jar test results demonstrated a decreasing trend in turbidity and dissolved organic carbon measurements with the increasing addition of alum. Optimum coagulant doses were selected based upon methods of analysis which involved identifying the point of diminishing return for each of the water sources. The optimum coagulant doses of alum selected were: 70 mg/L for both the Japanese Gardens and Perseverance and Cressbrook Dams water sources; 90 mg/L for the Cooby Dam water source; and 60 mg/L for the Mt Kynoch raw water mixture. Treating the water sources with these alum doses resulted in organic carbon removal percentages of 36.2 percent, 33.1 percent, 32.0 percent, and 37.8 percent respectively. These jar tests were replicated to verify the results. Equations were developed for each water source to theoretically predict the residual organic carbon from the coagulant dose. When treating the water samples with the selected optimum coagulant doses, the predicted residual organic carbon concentrations left untreated are 2.41 mg/L, 4.42 mg/L, 3.91 mg/L and 4.34 mg/L for the Japanese Gardens, Cooby Dam, Perseverance and Cressbrook Dams, Mt Kynoch raw water mixture water sources respectively. The trihalomethane formation potential of the untreated water samples were measured to be: 132 ppb for the Japanese Gardens water; 209 ppb for the Cooby Dam water source; 250 ppb for Perseverance and Cressbrook Dams; and 231 ppb for the Mt Kynoch raw water mixture. Treating these water samples with the selected optimum coagulant dosages reduced the trihalomethane formation potentials to 22 ppb, 91 ppb, 146 ppb and 82 ppb respectively. This research has contributed to quantifying the natural organic matter within Toowoomba’s water sources, and investigating the removal of this by enhanced coagulation. Further research is recommended to better understand in more detail the topics covered by this dissertation

Insights into mechanism and selectivity in ruthenium(II)-catalysed ortho-arylation reactions directed by Lewis basic groups

We report a detailed study of the selectivity of ruthenium-catalysed C-H arylation reactions directed by Lewis basic heterocycles. A reactivity scale for directing power in these reactions, based on the results of intermolecular competition experiments, is reported for the first time. Our work is supported by detailed density functional theory calculations that reveal the underlying mechanism of this reaction, which requires the dissociation of a p-cymene ligand before oxidative addition becomes competent. The calculated energetic span of the catalytic cycles for each substrate is broadly in agreement with our experimental observations. This work advances our understanding of mechanism and selectivity in these reactions, and provides a basis for future catalyst design efforts

Synthetic, structural and magnetic implications of introducing 2,2’-dipyridylamide to sodium-ferrate complexes

Using a transamination approach to access novel Fe(II) complexes, this study presents the synthesis, X-ray crystallographic and magnetic characterisation of a series of new iron complexes containing the multifunctional 2,2-dipyridylamide (DPA) ligand using iron bis(amide) [{Fe(HMDS)2}2] and sodium ferrate [{NaFe(HMDS)3}∞] (1) as precursors (HMDS = 1,1,1,3,3,3-hexamethyldisilazide). Reactions of DPA(H) with 1 show exceptionally good stoichiometric control, allowing access to heteroleptic [(THF)2·NaFe(DPA)(HMDS)2] (3) and homoleptic [{THF·NaFe(DPA)3}∞] (4) by using 1 and 3 equivalents of DPA(H) respectively. Linking this methodology and co-complexation, which is a more widely used approach to prepare heterobimetallic complexes, 3 can also be prepared by combining NaHMDS with heteroleptic [{Fe(DPA)(HMDS)}2] (2). In turn, 2 has been also synthesised and structurally defined by reacting [{Fe(HMDS)2}2] with two equivalents of DPA(H). Structural studies demonstrate the coordination flexibility of the N-bridged bis(heterocycle) ligand DPA, with 2 and 3 exhibiting discrete monomeric motifs, whereas 4 displays a much more intricate supramolecular structure, with one of its DPA ligands coordinating in an anti/anti fashion (as opposed to 2 and 3 where DPA shows a syn/syn conformation), which facilitates propagation of the structure via its central amido N. Magnetic studies confirmed the high-spin electron configuration of the iron(II) centres in all three compounds and revealed the existence of weak ferromagnetic interactions in dinuclear compound 2 (J = 1.01 cm-1)

Are chimpanzees really so poor at understanding imperative pointing? Some new data and an alternative view of canine and ape social cognition

There is considerable interest in comparative research on different species’ abilities to respond to human communicative cues such as gaze and pointing. It has been reported that some canines perform significantly better than monkeys and apes on tasks requiring the comprehension of either declarative or imperative pointing and these differences have been attributed to domestication in dogs. Here we tested a sample of chimpanzees on a task requiring comprehension of an imperative request and show that, though there are considerable individual differences, the performance by the apes rival those reported in pet dogs. We suggest that small differences in methodology can have a pronounced influence on performance on these types of tasks. We further suggest that basic differences in subject sampling, subject recruitment and rearing experiences have resulted in a skewed representation of canine abilities compared to those of monkeys and apes

Stakeholder views regarding ethical issues in the design and conduct of pragmatic trials : study protocol

This work is supported by the Canadian Institutes of Health Research through the Project Grant competition (competitive, peer reviewed), award number PJT-153045. Jeremy Grimshaw holds a Canada Research Chair in Health Knowledge Transfer and Uptake and a CIHR Foundation Grant (FDN-143269). Charles Weijer holds a Canada Research Chair in Bioethics. Joanne McKenzie is supported by an Australian National Health and Medical Research Council Career Development Fellowship (1143429). Vipul Jairath hold a personal Endowed Chair at Western University (John and Susan McDonald Endowed Chair). Marion Campbell is based with the Health Services Research Unit which is core-funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. Ian Graham is a CIHR Foundation Grant recipient (FDN# 143237).Peer reviewedPublisher PD

ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. FGFR1 signaling induces upregulation of Zinc-finger E-box-binding homeobox 1 (ZEB1) via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GB

2018 Research & Innovation Day Program

A one day showcase of applied research, social innovation, scholarship projects and activities.https://first.fanshawec.ca/cri_cripublications/1005/thumbnail.jp

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707