Electrochemiluminescence of a First-Row d6 Transition Metal Complex.

We report the electrochemiluminescence (ECL) of a 3d6 Cr(0) complex ([Cr(LMes)3]; λem=735 nm) with comparable photophysical properties to those of ECL-active complexes of 4d6 or 5d6 precious metal ions. The electrochemical potentials of [Cr(LMes)3] are more negative than those of [Ir(ppy)3] and render the [Cr(LMes)3]* excited state inaccessible through conventional co-reactant ECL with tri-n-propylamine or oxalate. ECL can be obtained, however, through the annihilation route in which potentials sufficient to oxidise and reduce the luminophore are alternately applied. When combined with [Ir(ppy)3] (λem=520 nm), the annihilation ECL of [Cr(LMes)3] was greatly enhanced whereas that of [Ir(ppy)3] was diminished. Under appropriate conditions, the relative intensities of the two spectrally distinct emissions can be controlled through the applied potentials. From this starting point for ECL with 3d6 metal complexes, we discuss some directions for future development.

Bimodal Electrochemiluminescence Microscopy of Single Cells.

Electrochemiluminescence (ECL) microscopy is an emerging technique with new applications such as imaging of single entities and cells. Herein, we have developed a bimodal and bicolor approach to record both positive ECL (PECL: light-emitting object on dark background) and shadow label-free ECL (SECL: nonemissive object shadowing the background luminescence) images of single cells. This bimodal approach is the result of the simultaneous emissions of [Ru(bpy)3]2+ used to label the cellular membrane (PECL) and [Ir(sppy)3]3- dissolved in solution (SECL). By spectrally resolving the ECL emission wavelengths, we recorded the images of the same cells in both PECL and SECL modes using the [Ru(bpy)3]2+ (λmax = 620 nm) and [Ir(sppy)3]3- (λmax = 515 nm) luminescence, respectively. PECL shows the distribution of the [Ru(bpy)3]2+ labels attached to the cellular membrane, whereas SECL reflects the local diffusional hindrance of the ECL reagents by each cell. The high sensitivity and surface-confined features of the reported approach are demonstrated by imaging cell-cell contacts during the mitosis process. Furthermore, the comparison of PECL and SECL images demonstrates the differential diffusion of tri-n-propylamine and [Ir(sppy)3]3- through the permeabilized cell membranes. Consequently, this dual approach enables the imaging of the morphology of the cell adhering on the surface and can significantly contribute to multimodal ECL imaging and bioassays with different luminescent systems.

Extending Photocatalyst Activity through Choice of Electron Donor.

Sacrificial additives are commonly employed in photoredox catalysis as a convenient source of electrons, but what occurs after electron transfer is often overlooked. Tertiary alkylamines initially form radical cations following electron transfer, which readily deprotonate to form strongly reducing, neutral α-amino radicals. Similarly, the oxalate radical anion (C2O4•-) rapidly decomposes to form CO2•- (E0 ≈ -2.2 V vs SCE). We show that not only are these reactive intermediates formed under photoredox conditions, but they can also impact the desired photochemistry, both positively and negatively. Photoredox systems using oxalate as an electron donor are able to engage substrates with greater energy demands, extending reactivity past the energy limits of single and multiphoton transition metal catalysts. Furthermore, oxalate offers better chemoselectivity than the commonly employed triethylamine when reducing substrates with moderate energy requirements.

Using Nitroxides to Enhance Carbon Fiber Interfacial Adhesion and as an Anchor for "Graft to" Surface Modification Strategies.

Nitroxide groups covalently grafted to carbon fibers are used as anchoring sites for TEMPO-terminated polymers (poly-n-butylacrylate and polystyrene) in a "graft to" surface modification strategy. All surface-modified fibers are evaluated for their physical properties, showing that several treatments have enhanced the tensile strength and Young's modulus compared to the control fibers. Up to an 18% increase in tensile strength and 12% in Young's modulus are observed. Similarly, the evaluation of interfacial shear strength in an epoxy polymer shows improvements of up to 144% relative to the control sample. Interestingly, the polymer-grafted surfaces show smaller increases in interfacial shear strength compared to surfaces modified with a small molecule only. This counterintuitive result is attributed to the incompatibility, both chemical and physical, of the grafted polymers to the surrounding epoxy matrix. Molecular dynamics simulations of the interface suggest that the diminished increase in mechanical shear strength observed for the polymer grafted surfaces may be due to the lack of exposed chain ends, whereas the small molecule grafted interface exclusively presents chain ends to the resin interface, resulting in good improvements in mechanical properties.

Reinterpreting the Fate of Iridium(III) Photocatalysts─Screening a Combinatorial Library to Explore Light-Driven Side-Reactions.

Photoredox catalysts are primarily selected based on ground and excited state properties, but their activity is also intrinsically tied to the nature of their reduced (or oxidized) intermediates. Catalyst reactivity often necessitates an inherent instability, thus these intermediates represent a mechanistic turning point that affords either product formation or side-reactions. In this work, we explore the scope of a previously demonstrated side-reaction that partially saturates one pyridine ring of the ancillary ligand in heteroleptic iridium(III) complexes. Using high-throughput synthesis and screening under photochemical conditions, we identified different chemical pathways, ultimately governed by ligand composition. The ancillary ligand was the key factor that determined photochemical stability. Following photoinitiated electron transfer from a sacrificial tertiary amine, the reduced intermediate of complexes containing 1,10-phenanthroline derivatives exhibited long-term stability. In contrast, complexes containing 2,2'-bipyridines were highly susceptible to hydrogen atom transfer and ancillary ligand modification. Detailed characterization of selected complexes before and after transformation showed differing effects on the ground and excited state reduction potentials dependent on the nature of the cyclometalating ligands and excited states. The implications of catalyst stability and reactivity in chemical synthesis was demonstrated in a model photoredox reaction.

Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review.

Objectives: Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods: The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results: This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion: Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.

The Tandem Photoredox Catalysis Mechanism of [Ir(ppy)2(dtb-bpy)]+ Enabling Access to Energy Demanding Organic Substrates.

We report the discovery of a tandem catalytic process to reduce energy demanding substrates, using the [Ir(ppy)2(dtb-bpy)]+ (1+) photocatalyst. The immediate products of photoinitiated electron transfer (PET) between 1+ and triethylamine (TEA) undergo subsequent reactions to generate a previously unknown, highly reducing species (2). Formation of 2 occurs via reduction and semisaturation of the ancillary dtb-bpy ligand, where the TEA radical cation serves as an effective hydrogen atom donor, confirmed by nuclear magnetic resonance, mass spectrometry, and deuterium labeling experiments. Steady-state and time-resolved luminescence and absorption studies reveal that upon irradiation, 2 undergoes electron transfer or proton-coupled electron transfer (PCET) with a representative acceptor (N-(diphenylmethylene)-1-phenylmethanamine; S). Turnover of this new photocatalytic cycle occurs along with the reformation of 1+. We rationalize our observations by proposing the first example of a mechanistic pathway where two distinct yet interconnected photoredox cycles provide access to an extended reduction potential window capable of engaging a wide range of energy demanding and synthetically relevant organic substrates including aryl halides.

N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.

Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system xc- In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system xc- and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system xc- and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders.

Deficiency of selenoprotein S, an endoplasmic reticulum resident oxidoreductase, impairs the contractile function of fast-twitch hindlimb muscles.

Selenoprotein S (Seps1) is an endoplasmic reticulum (ER) resident antioxidant implicated in ER stress and inflammation. In human vastus lateralis and mouse hindlimb muscles, Seps1 localization and expression were fiber-type specific. In male Seps1+/- heterozygous mice, spontaneous physical activity was reduced compared with wild-type littermates ( d = 1.10, P = 0.029). A similar trend was also observed in Seps1-/- knockout mice ( d = 1.12, P = 0.051). Whole body metabolism, body composition, extensor digitorum longus (EDL), and soleus mass and myofiber diameter were unaffected by genotype. However, in isolated fast EDL muscles from Seps1-/- knockout mice, the force frequency curve (FFC; 1-120 Hz) was shifted downward versus EDL muscles from wild-type littermates ( d = 0.55, P = 0.002), suggestive of reduced strength. During 4 min of intermittent, submaximal (60 Hz) stimulation, the genetic deletion or reduction of Seps1 decreased EDL force production ( d = 0.52, P < 0.001). Furthermore, at the start of the intermittent stimulation protocol, when compared with the 60-Hz stimulation of the FFC, EDL muscles from Seps1-/- knockout or Seps1+/- heterozygous mice produced 10% less force than those from wild-type littermates ( d = 0.31, P < 0.001 and d = 0.39, P = 0.015). This functional impairment was associated with reduced mRNA transcript abundance of thioredoxin-1 ( Trx1), thioredoxin interacting protein ( Txnip), and the ER stress markers Chop and Grp94, whereas, in slow soleus muscles, Seps1 deletion did not compromise contractile function and Trx1 ( d = 1.38, P = 0.012) and Txnip ( d = 1.27, P = 0.025) gene expression was increased. Seps1 is a novel regulator of contractile function and cellular stress responses in fast-twitch muscles.

Modification of Carbon Fibre Surfaces by Sulfur-Fluoride Exchange Click Chemistry.

Technologies that enable surface modification are in high demand and are critical for the implementation of new functional materials and devices. Here, we describe the first modification of a carbon surface (in this case carbon fiber) using the sulfur-fluoride exchange (SuFEx) reaction. The parent sulfur (VI) fluoride moiety can be installed directly to the surface via electrochemical deposition of the fluorosulfate phenyldiazonium tetrafluoroborate salt, or by 'SuFExing' a phenol on the carbon surface followed by treatment of the material with SO2 F2 ; similar to a 'graft to' or 'graft from' functionalization approach. We demonstrate that these SuFEx-able surfaces readily undergo exchange with aryl silyl ethers, and that the subsequent sulfate linkages are themselves stable under electrochemical redox conditions. Finally, we showcase the utility of the SuFEx chemistry by installing a pendant amino group to the fiber surface resulting in interfacial shear strength improvements of up to 130 % in epoxy resin.

Simultaneously 'pushing' and 'pulling' graphene oxide into low-polar solvents through a designed interface.

Dispersing graphene oxide (GO) in low-polar solvents can realize a perfect self-assembly with functional molecules and application in removal of organic impurities that only dissolve in low-polar solvents. The surface chemistry of GO plays an important role in its dispersity in these solvents. The direct transfer of hydrophilic GO into low-polar solvents, however, has remained an experimental challenge. In this study, we design an interface to transfer GO by simultaneously 'pushing and pulling' the nanosheets into low-polar solvents. Our approach is outstanding due to the ability to obtain monolayers of chemically reduced GO (CRGO) with designed surface properties in the organic phase. Using the transferred GO or CRGO dispersions, we have fabricated GO/fullerene nanocomposites and assessed the ability of CRGOs for dye adsorption. We hope our work can provide a universal approach for the phase transfer of other nanomaterials.

Mixed annihilation electrogenerated chemiluminescence of iridium(iii) complexes.

Previously reported annihilation ECL of mixtures of metal complexes have generally comprised Ir(ppy)3 or a close analogue as a higher energy donor/emitter (green/blue light) and [Ru(bpy)3]2+ or its derivative as a lower energy acceptor/emitter (red light). In contrast, here we examine Ir(ppy)3 as the lower energy acceptor/emitter, by combining it with a second Ir(iii) complex: [Ir(df-ppy)2(ptb)]+ (where ptb = 1-benzyl-1,2,3-triazol-4-ylpyridine). The application of potentials sufficient to attain the first single-electron oxidation and reduction products can be exploited to detect Ir(ppy)3 at orders of magnitude lower concentration, or enhance its maximum emission intensity at high concentration far beyond that achievable through conventional annihilation ECL of Ir(ppy)3 involving comproportionation. Moreover, under certain conditions, the colour of the emission can be selected through the applied electrochemical potentials. We have also prepared a novel Ir(iii) complex with a sufficiently low reduction potential that the reaction between its reduced form and Ir(ppy)3+ cannot populate the excited state of either luminophore. This enabled, for the first time, the exclusive formation of either excited state through the application of higher cathodic or anodic potentials, but in both cases, the ECL was greatly diminished by parasitic dark reactions.

Considering the chemical energy requirements of the tri-n-propylamine co-reactant pathways for the judicious design of new electrogenerated chemiluminescence detection systems.

The introduction of a 'co-reactant' was a critical step in the evolution of electrogenerated chemiluminescence (ECL) from a laboratory curiosity to a widely utilised detection system. In conjunction with a suitable electrochemiluminophore, the co-reactant enables generation of both the oxidised and reduced precursors to the emitting species at a single electrode potential, under the aqueous conditions required for most analytical applications. The most commonly used co-reactant is tri-n-propylamine (TPrA), which was developed for the classic tris(2,2'-bipyridine)ruthenium(II) ECL reagent. New electrochemiluminophores such as cyclometalated iridium(III) complexes are also evaluated with this co-reactant. However, attaining the excited states in these systems can require much greater energy than that of tris(2,2'-bipyridine)ruthenium(II), which has implications for the co-reactant reaction pathways. In this tutorial review, we describe a simple graphical approach to characterise the energetically feasible ECL pathways with TPrA, as a useful tool for the development of new ECL detection systems.

Analytically useful blue chemiluminescence from a water-soluble iridium(III) complex containing a tetraethylene glycol functionalised triazolylpyridine ligand.

We examine [Ir(df-ppy)2(pt-TEG)](+) as the first highly water soluble, blue-luminescent iridium(III) complex for chemiluminescence detection. Marked differences in selectivity were observed between the new complex and the conventional [Ru(bpy)3](2+) reagent, which will enable this mode of detection to be extended to new areas of application.

N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms.

BACKGROUND: Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ. METHODS: This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes. DISCUSSION: This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.

Blue Electrogenerated Chemiluminescence from Water-Soluble Iridium Complexes Containing Sulfonated Phenylpyridine or Tetraethylene Glycol Derivatized Triazolylpyridine Ligands.

Incorporating phenylpyridine- and triazolylpyridine-based ligands decorated with methylsulfonate or tetraethylene glycol (TEG) groups, a series of iridium(III) complexes has been created for green and blue electrogenerated chemiluminescence under analytically useful aqueous conditions, with tri-n-propylamine as a coreactant. The relative electrochemiluminescence (ECL) intensities of the complexes were dependent on the sensitivity of the photodetector over the wavelength range and the pulse time of the applied electrochemical potential. In terms of the integrated area of corrected ECL spectra, with a pulse time of 0.5 s, the intensities of the Ir(III) complexes were between 18 and 102 % that of [Ru(bpy)3 ](2+) (bpy=2,2'-bipyridine). However, when the intensities were measured with a typical bialkali photomultiplier tube, the signal of the most effective blue emitter, [Ir(df-ppy)2 (pt-TEG)](+) (df-ppy=2-(2,4-difluorophenyl)pyridine anion, pt-TEG=1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-4-(2-pyridyl)-1,2,3-triazole), was over 1200 % that of the orange-red emitter [Ru(bpy)3 ](2+) . A combined experimental and theoretical investigation of the electrochemical and spectroscopic properties of the Ir(III) complexes indicated that the greater intensity from [Ir(df-ppy)2 (pt-TEG)](+) relative to those of the other Ir(III) complexes resulted from a combination of many factors, rather than being significantly favored in one area.

Electrogenerated chemiluminescence of tris(2,2' bipyridine)ruthenium(II) using common biological buffers as co-reactant, pH buffer and supporting electrolyte.

A series of aliphatic tertiary amines (HEPES, POPSO, EPPS and BIS-TRIS) commonly used to buffer the pH in biological experiments, were examined as alternative, non-toxic co-reactants for the electrogenerated chemiluminescence (ECL) of tris(2,2'-bipyridine)ruthenium(ii) ([Ru(bpy)3](2+)). These were found to be very attractive as "multi-tasking" reagents, serving not only as co-reactants, but also fulfiling the roles of pH buffer and supporting electrolyte within an aqueous environment; thus significantly simplifying the overall ECL analysis. Sub-nanomolar detection limits were obtained for [Ru(bpy)3](2+) in the presence of BIS-TRIS, making this species an valuable option for co-reactant ECL-based bioanalytical applications.

Red-green-blue electrogenerated chemiluminescence utilizing a digital camera as detector.

Exploiting the distinct excitation and emission properties of concomitant electrochemiluminophores in conjunction with the inherent color selectivity of a conventional digital camera, we create a new strategy for multiplexed electrogenerated chemiluminescence detection, suitable for the development of low-cost, portable clinical diagnostic devices. Red, green and blue emitters can be efficiently resolved over the three-dimensional space of ECL intensity versus applied potential and emission wavelength. As the relative contribution ratio of each emitter to the photographic RGB channels is constant, the RGB ECL intensity versus applied-potential curves could be effectively isolated to a single emitter at each potential.

Control of excitation and quenching in multi-colour electrogenerated chemiluminescence systems through choice of co-reactant.

We demonstrate a new approach to manipulate the selective emission in mixed electrogenerated chemiluminescence (ECL) systems, where subtle changes in co-reactant properties are exploited to control the relative electron-transfer processes of excitation and quenching. Two closely related tertiary-amine co-reactants, tri-n-propylamine and N,N-diisopropylethylamine, generate remarkably different emission profiles: one provides distinct green and red ECL from [Ir(ppy)3] (ppy=2-phenylpyridinato-C2,N) and a [Ru(bpy)3](2+) (bpy=2,2'-bipyridine) derivative at different applied potentials, whereas the other generates both emissions simultaneously across a wide potential range. These phenomena can be rationalized through the relative exergonicities of electron-transfer quenching of the excited states, in conjunction with the change in concentration of the quenchers over the applied potential range.

Understanding electrogenerated chemiluminescence efficiency in blue-shifted iridium(III)-complexes: an experimental and theoretical study.

Compared to tris(2-phenylpyridine)iridium(III) ([Ir(ppy)3 ]), iridium(III) complexes containing difluorophenylpyridine (df-ppy) and/or an ancillary triazolylpyridine ligand [3-phenyl-1,2,4-triazol-5-ylpyridinato (ptp) or 1-benzyl-1,2,3-triazol-4-ylpyridine (ptb)] exhibit considerable hypsochromic shifts (ca. 25-60 nm), due to the significant stabilising effect of these ligands on the HOMO energy, whilst having relatively little effect on the LUMO. Despite their lower photoluminescence quantum yields compared with [Ir(ppy)3 ] and [Ir(df-ppy)3 ], the iridium(III) complexes containing triazolylpyridine ligands gave greater electrogenerated chemiluminescence (ECL) intensities (using tri-n-propylamine (TPA) as a co-reactant), which can in part be ascribed to the more energetically favourable reactions of the oxidised complex (M(+) ) with both TPA and its neutral radical oxidation product. The calculated iridium(III) complex LUMO energies were shown to be a good predictor of the corresponding M(+) LUMO energies, and both HOMO and LUMO levels are related to ECL efficiency. The theoretical and experimental data together show that the best strategy for the design of efficient new blue-shifted electrochemiluminophores is to aim to stabilise the HOMO, while only moderately stabilising the LUMO, thereby increasing the energy gap but ensuring favourable thermodynamics and kinetics for the ECL reaction. Of the iridium(III) complexes examined, [Ir(df-ppy)2 (ptb)](+) was most attractive as a blue-emitter for ECL detection, featuring a large hypsochromic shift (λmax =454 and 484 nm), superior co-reactant ECL intensity than the archetypal homoleptic green and blue emitters: [Ir(ppy)3 ] and [Ir(df-ppy)3 ] (by over 16-fold and threefold, respectively), and greater solubility in polar solvents.