ATRP catalysts of tetradentate guanidine ligands - do guanidine donors induce a faster atom transfer?

Tripodal tetradentate N donor ligands stabilise the most active ATRP catalyst systems. Here, we set out to synthesise the new guanidine ligand TMG-4NMe2uns-penp, inspired by p-substituted tris(2-pyridylmethyl)amine (TPMA) ligands. The impact of changing pyridine against guanidine donors was examined through solid state and solution experiments and density functional theory (DFT) calculations. In the solid state, the molecular structures of copper complexes based on the ligands TMG-4NMe2uns-penp, TMG-uns-penp and TMG3tren were discussed concerning the influence of a NMe2 substituent at the pyridines and the guanidine donors. In solution, the TMG-4NMe2uns-penp system was investigated by several methods, including UV/Vis, EPR and NMR spectroscopy indicating similar properties to that of the highly active TPMANMe2 system. The redox potentials were determined and related to the catalytic activity. Besides the expected trends between these and the ligand structures, there is evidence that guanidine donors in tripodal ligand systems lead to a better deactivation and possibly a faster exchange within the ATRP equilibrium than TPMA systems. Supported by DFT calculations, it derives from an easier cleavable Cu-Br bond of the copper(II) deactivator species. The high activity was stated by a controlled initiator for continuous activator regeneration (ICAR) ATRP of styrene.

The bridge towards a more stable and active side-on-peroxido (Cu2II(µ-η2:η2-O2)) complex as a tyrosinase model system.

A novel dinucleating bis(pyrazolyl)methane ligand was developed for tyrosinase model systems. After ligand synthesis, the corresponding Cu(I) complex was synthesized and upon oxygenation, formation of a µ-η2:η2 peroxido complex could be observed and monitored using UV/Vis-spectroscopy. Due to the high stability of this species even at room temperature, a molecular structure of the complex could be characterized via single-crystal XRD. Additional to its promising stability, the peroxido complex showed catalytic tyrosinase activity which was investigated via UV/Vis-spectroscopy. Products of the catalytic conversion could be isolated and characterized and the ligand could be successfully recycled after catalysis experiments. Furthermore, the peroxido complex was reduced by reductants with different reduction potentials. The characteristics of the electron transfer reactions were investigated with the help of the Marcus relation. The combination of the high stability and catalytic activity of the peroxido complex with the new dinucleating ligand, enables the shift of oxygenation reactions for selected substrates towards green chemistry, which is furthered by the efficient ligand recycling capability.

Formate complexes of tri- and tetravalent titanium supported by a tris(phenolato)amine ligand.

Titanium(III) and titanium(IV) formate complexes supported by the sterically encumbering tris(phenolato)amine ligand (H3(O3N) = tris(4,6-di-tert-butyl-2-hydroxybenzyl)amine) are described. Salt metathesis of the chlorido precursor [(O3N)TiCl] (1-Cl) with sodium formate in a 2 : 1 ratio in THF gave a dimer of sodium dititanium triformate units with 12-membered ring [Na{(O3N)Ti}2(µ-OCHO-ηO:ηO')3]2 (3-Na) when crystallized from acetonitrile. Complex 3-Na was also prepared by reacting the previously reported terminal formate complex [(O3N)Ti(OCHO)] (2) with excess sodium formate. Salt metathesis of 1-Cl with potassium formate gave a tetratitanium cluster of the composition [K3{(O3N)Ti}4(OCHO)7] (3-K) which can be also obtained by treating 2 with potassium formate. In 3-K both Ti and K centers are six-coordinate. The titanium(III) complexes [(O3N)Ti(L)] (4-L, L = THF, THP, Et2O) and solvent free dimeric [(O3N)Ti]2 (5) were synthesized by reduction of 1-Cl with sodium sand or magnesium in THF, THP, Et2O, and n-pentane, respectively. The tert-butyl formate adduct of titanium(III)-[(O3N)Ti(tBuOCHO)] (6) was isolated by reacting 4-L or 5 with tert-butyl formate. Complex 6 is thermolabile and slowly decomposed in solution to produce a formate-bridged mixed-valence titanium(III)/titanium(IV) complex [{(O3N)Ti}2(µ-OCHO-ηO:ηO')] (7) which further decomposed to a mixture containing 2, [(O3N)Ti(OH)] and [(O3N)Ti-O-Ti(O3N)]. All new complexes were isolated in moderate to good yields and fully characterized by elemental analysis, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction analysis. For the titanium(III) complexes solution magnetic moments were measured by the Evans method and EPR spectra recorded as toluene glass at 77 K.

Understanding the structure-activity relationship and performance of highly active novel ATRP catalysts.

Copper bromide complexes based on a series of substituted guanidine-quinolinyl and -pyridinyl ligands are reported. The ligand systems were chosen based on the large variation with regard to their flexibility in the backbone, different guanidine moieties and influence by electron density donating groups. Relationships between the molecular structures and spectroscopic and electronic properties are described. Beside the expected increase in activity by substituting the 4-position (NMe2vs. H), we showed that a higher flexibility, such as TMG vs. DMEG moiety, leads to a better stabilsiation of the copper(II) complex. Due to the correlation of the potentials and KATRP values, the catalyst based on the ligand TMGm4NMe2py is the most active copper complex for ATRP with a bidentate ligand system. The combination of the strong donating abilities of dimethylamine pyridinyl, the donor properties of the TMG substituent, and the improved flexibility due to the methylene bridging unit leads to high activity. With all NMe2-substituted systems standard ATRP experiments were conducted and with more active NMe2-substituted pyridinyl systems, ICAR ATRP experiments of styrene were conducted. Low dispersities and ideal molar masses have been achieved.

Evaluation of eye metrics as a detector of fatigue.

OBJECTIVES: This study evaluated oculometrics as a detector of fatigue in Air Force-relevant tasks after sleep deprivation. Using the metrics of total eye closure duration (PERCLOS) and approximate entropy (ApEn), the relation between these eye metrics and fatigue-induced performance decrements was investigated. BACKGROUND: One damaging effect to the successful outcome of operational military missions is that attributed to sleep deprivation-induced fatigue. Consequently, there is interest in the development of reliable monitoring devices that can assess when an operator is overly fatigued. METHOD: Ten civilian participants volunteered to serve in this study. Each was trained on three performance tasks: target identification, unmanned aerial vehicle landing, and the psychomotor vigilance task (PVT). Experimental testing began after 14 hr awake and continued every 2 hr until 28 hr of sleep deprivation was reached. RESULTS: Performance on the PVT and target identification tasks declined significantly as the level of sleep deprivation increased.These performance declines were paralleled more closely by changes in the ApEn compared to the PERCLOS measure. CONCLUSION: The results provide evidence that the ApEn eye metric can be used to detect fatigue in relevant military aviation tasks. APPLICATION: Military and commercial operators could benefit from an alertness monitoring device.

Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability.

The mammalian target of rapamycin (mTOR) regulates cellular growth and proliferation, mainly by controlling cellular translation. Most tumors show constitutive activation of the mTOR pathway. In hypoxia, mTOR is inactivated, which is believed to be part of the program of the cell to maintain energy homeostasis. However, certain proteins are believed to be preferentially translated during hypoxia via 5' terminal oligopyrimidine tract mechanisms with controversial discussion about the involvement of the mTOR-dependent ribosomal protein S6 (rpS6). The hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxic adaptation and itself strongly implicated in tumor growth. HIF is translationally regulated by mTOR. The regulatory features and the involvement of molecular oxygen itself in this regulation of HIF by mTOR are poorly understood. mTOR inhibition leads to profound attenuation of HIFalpha protein in the majority of primary and cancer cells studied. Under severe hypoxia, no influence of mTOR inhibitors was observed; thus, stimulation of HIFalpha by mTOR may only be relevant under mild hypoxia or even normoxia. HIF expression and phosphorylated rpS6 negatively correlate in experimental tumors. In cell culture, prolonged hypoxia abolishes rpS6 phosphorylation, which seems to be partly independent of the upstream p70S6 kinase. We show that hypoxic repression of rpS6 is largely dependent on HIF, implicating a negative feedback loop, which may influence cellular translational rates and metabolic homeostasis. These data implicate that the hypoxic microenvironment renders tumor cells resistant to mTOR inhibition, at least concerning hypoxic gene activation, which would add to the difficulties of other established therapeutic strategies in hypoxic cancer tissues.

Alertness management strategies for operational contexts.

This review addresses the problem of fatigue (on-the-job-sleepiness) attributable to sleep loss in modern society and the scientifically proven strategies useful for reducing fatigue-related risks. Fatigue has become pervasive because many people work non-standard schedules, and/or they consistently fail to obtain sufficient sleep. Sleep restriction, sleep deprivation, and circadian desynchronization produce a variety of decrements in cognitive performance as well as an array of occupational and health risks. A number of real-world mishaps have resulted from performance failures associated with operator sleepiness. In some cases, fatigue/sleepiness is unavoidable, at least temporarily, due to job-related or other factors, but in other cases, fatigue/sleepiness results from poor personal choices. Furthermore, some individuals are more vulnerable to the effects of sleep loss than others. Fortunately, fatigue-related risks can be mitigated with scientifically valid alertness-management strategies. Proper work/rest scheduling and good sleep hygiene are of primary importance. If sleep time is available but sleep is difficult to obtain, sleep-inducing medications and behavioral circadian-adjustment strategies are key. In fatiguing situations such as when sleep opportunities are temporarily inadequate, limiting time on tasks, strategic napping, and the potential use of alertness-enhancing compounds must be considered. To optimize any alertness-management program, everyone must first be educated about the nature of the problem and the manner in which accepted remedies should be implemented. In the near future, objective fatigue-detection technologies may contribute substantially to the alleviation of fatigue-related risks in real-world operations.

Generating performance test batteries relevant to specific operational tasks.

The present review focuses on the development of a performance battery generation system that selects performance tests most applicable to particular jobs. First, a list or taxonomy of cognitive and performance skills that are involved in real-world jobs or missions is developed. Based on this list, an "armory" of performance tests probing those skills is identified. A new technique is then developed to select from that armory the minimum number of tests that optimally probe the demands of a specific job or mission. While specifics of these developments will continue to evolve, it is hoped that the general framework described here will help close the gap between laboratory testing and real-world tasks, and form the foundation of the way performance test batteries will be developed in the future.