Oriented Internal Electrostatic Fields Cooperatively Promote Ground- and Excited-State Reactivity: A Case Study in Photochemical CO2 Capture

Oriented electrostatic fields can exert catalytic effects upon both the kinetics and the thermodynamics of chemical reactions; however, the vast majority of studies thus far have focused upon ground-state chemistry and rarely consider any more than a single class of reaction. In the present study, we first use density functional theory (DFT) calculations to clarify the mechanism of CO2 storage via photochemical carboxylation of o-alkylphenyl ketones, originally proposed by Murakami et al. (J. Am. Chem. Soc.2015, 137, 14063); we then demonstrate that oriented internal electrostatic fields arising from remote charged functional groups (CFGs) can selectively and cooperatively promote both ground- and excited-state chemical reactivity at all points along the revised mechanism, in a manner otherwise difficult to access via classical substituent effects. What is particularly striking is that electrostatic field effects upon key photochemical transitions are predictably enhanced in increasingly polar solvents, thus overcoming a central limitation of the electrostatic catalysis paradigm. We explain these observations, which should be readily extendable to the ground state.We acknowledge financial support from the Australian Research Council (ARC) Centre of Excellence for Electromaterials Science (CE140100012, FL170100041), an ARC Laureate Fellowship (to M.L.C.), and generous supercomputing time from the National Computational Infrastructure. M.T.B. acknowledges an Australian Government Research Training Program Scholarship and Dean’s Merit Scholarship in Science. We also wish to thank Vincent Doan for helpful discussions

The effects of Lewis acid complexation on type I radical photoinitiators and implications for pulsed laser polymerization

MLC gratefully acknowledges support from the Australian Research Council under its Discovery Projects program (DP150104454) and generous allocations of supercomputing time on the National Facility of the Australian National Computational Infrastructur

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19

Isotactic Regulation in the Radical Polymerization of Calcium Methacrylate: Is Multiple Chelation the Key to Stereocontrol?

Accurate quantum chemistry is used to explain the origins of isospecificity in radical polymerization of calcium methacrylate hydrate (CaMA). Distonic radical-cation interactions are shown to be crucial in determining the reactivity of different coordination structures. Cation coordination to the terminal and incoming monomer side chains reduces radical‐cation separation, enhancing the reactivity of these modes over the stereocontrolling terminal‐penultimate binding modes. This explains why Lewis acid‐mediated radical polymerization often fails to produce highly isotactic polymer for common monomers such as methyl methacrylate. However, theoretical calculations suggest that the poly(CaMA) terminus forms a chelated bridging scaffold in N,N‐dimethylformamide (DMF), which involves the terminal, penultimate and incoming monomer carboxylate groups. This scaffold simultaneously activates the incoming monomer toward propagation and regulates the relative orientation of the terminal and penultimate side chains. The bridging scaffold is disrupted in more polar solvents and/or if alternative nonchelating counter‐cations are employed, leading to loss of isotactic control. These results suggest that higher levels of isotactic control may be achievable if reaction conditions are optimized to favor bridging scaffold formation. The broader importance of these findings to stereocontrol in radical polymerization is also discussed.The authors gratefully acknowledge generous allocations of supercomputing time on the National Facility of the National Computational Infrastructure (NCI), and financial support from the Australian Research Council (ARC)

A digital approach in the rapid response to COVID-19-Experience of a paediatric institution

INTRODUCTION: COVID-19 has radically changed the delivery of healthcare in Australia. Central to a tertiary paediatric institution's (The Royal Children's Hospital Melbourne (RCH) response was a digital health approach comprising a broad suite of informatics and technology solutions including optimising a fully integrated electronic medical record (EMR). METHODS: This comprehensive approach spanned all patient care areas and encompassed a broad range of hospital operations. They included patient triage, registration, COVID-19 screening clinic operations, electronic ordering, prescribing and documentation, telehealth, reporting and analytics and research. DISCUSSION: This paper outlines key aspects of our COVID-19 digital health strategy, highlighting the rapid transition to telehealth and the development of a remote "virtual telehealth" strategy for clinicians which proved popular and allowed true "working from home". CONCLUSION: COVID-19 has inadvertently focussed the spotlight on the utility of digital health for clinical care. The speed and uptake of digital health within this pandemic has been remarkable and unprecedented in both an Australian and global setting. Whilst many of these changes have been beneficial, some may have been rushed or forced with minimal consideration of ongoing governance. Key stakeholders and enablers should be identified for post-pandemic consideration in future digital health implementation and adoption strategies

Mechanistic Insights into N-Acyloxyamine-Initiated Controlled Degradation of Polypropylene: The Unexpected Role of Keto-Enol Tautomerization in Carboxylate Radical Chemistry

Controlled degradation of polypropylene (PP) is used industrially to improve the properties of crude PP. While this degradation is traditionally initiated by organic peroxides, N-acyloxyamines are now preferred due to their greater stability. However, their mechanism of action remains unclear. Using high-level ab initio calculations, we show that N-O homolysis is the most likely fragmentation pathway available to N-acyloxyamines, in contrast to the more usual C-O homolysis observed for the closely related N-alkoxyamines. This would, in theory, generate aminyl and carboxylate radicals, with the latter undergoing decarboxylation to generate methyl radicals. However, the enol forms of N-acyloxyamines are significantly less thermally stable, having bond dissociation free energies that are over 50 kJ/mol below those of their keto equivalents. Under conditions where keto-enol tautomerism is feasible, enol N-O homolysis, which forms the more stable acetic acid radical, would be the dominant degradation pathway. This reveals the crucial and underappreciated role that polar impurities play in the initiation process of enolizable initiators and may explain contradictory observations in the experimental literature. The product aminyl radicals are susceptible to β-fragmentation, releasing alkyl radicals and affording imines, which in turn are susceptible to allylic H-abstraction and further β-fragmentation leading to dialkylpyridines as the ultimate degradation products.Australian Research Council (FL170100041) BASF

Computational Optimization of Alkoxyamine-based Electrochemical Methylation

Computational chemistry at the G3(MP2)-RAD//M06-2X/6-31+G(d,p)//SMD level of theory was used to study the oxidation of a test set of methyl adducts of nitroxide radicals and methyl adducts of Blatter's radical, a Kuhn verdazyl and two oxo-verdazyls. The barriers and the reaction energies of the SN2 reactions of the oxidized species with pyridine were also studied with a view to identify species with both low oxidation potentials and low SN2 barriers, so as to broaden the functional group tolerance of in situ electrochemical methylation compared with TEMPO-Me (1-methoxy-2,2,6,6-tetramethylpiperidine). Within the alkoxyamines, the oxidation potentials covered a range of 0.5 V, with trends explicable in terms of electrostatics, ring strain, and charge transfer. The oxidation potentials of oxo-verdazyl adducts, verdazyl adducts, and particularly the methyl adducts of Blatter's radical were considerably low due to the ability of their extensive π-systems to stabilize a positive charge. As expected, the SN2 reaction energies of the oxidized substrate became less favorable as the oxidation potential decreases. Unfortunately, this also meant that the barriers increased due to the excellent Evans-Polanyi correlation (R2 = 0.92). Nonetheless, 7-methoxy-7-azadispiro[5.1.5.836]hexadecane, N,N-di-tert-butyl-O-methylhydroxylamine, and particularly 1-methoxy-2,2,5,5-tetramethylpyrrolidine were identified as suitable candidates for broadening the scope of in situ electrochemical methylation while maintaining comparable kinetics to known reagents.Australian Research Council (FL170100041)