Oxygen-Sensing Chemiluminescent Iridium(III) 1,2-Dioxetanes: Unusual Coordination and Activity.

Next generation chemiluminescent iridium 1,2-dioxetane complexes have been developed which consist of the Schaap's 1,2-dioxetane scaffold directly attached to the metal center. This was achieved by synthetically modifying the scaffold precursor with a phenylpyridine moiety, which can act as a ligand. Reaction of this scaffold ligand with the iridium dimer [Ir(BTP)2(µ-Cl)]2 (BTP = 2-(benzo[b]thiophen-2-yl)pyridine) yielded isomers which depict ligation through either the cyclometalating carbon or, interestingly, the sulfur atom of one BTP ligand. Their corresponding 1,2-dioxetanes display chemiluminescent responses in buffered solutions, exhibiting a single, red-shifted peak at 600 nm. This triplet emission was effectively quenched by oxygen, yielding in vitro Stern-Volmer constants of 0.1 and 0.009 mbar-1 for the carbon-bound and sulfur compound, respectively. Lastly, the sulfur-bound dioxetane was further utilized for oxygen sensing in muscle tissue of living mice and xenograft models of tumor hypoxia, depicting the ability of the probe chemiluminescence to penetrate biological tissue (total flux ~ 106 p/s).

Energy Transfer Chemiluminescent Spiroadamantane 1,2-Dioxetane Probes for Bioanalyte Detection and Imaging.

Chemiluminescence imaging of bioanalytes using spiroadamantane 1,2-dioxetanes has gained significant attention due to improved signal-to-noise ratios and imaging depth compared to excitation-based probes, as well as their modifiable scaffolds that offer analyte-specific responses and tunable emissive properties. Among several strategies employed to amplify signals under aqueous conditions and to shift the emission into the bio-relevant red region, energy transfer to an adjacent fluorophore is a popular and effective method. This Minireview highlights spiroadamantane 1,2-dioxetane-based probes that operate via an energy transfer mechanism to detect bioanalytes both in vitro and in vivo. Probes that display both non-covalent and covalent interactions with fluorophores, as well as their applications in imaging specific analytes will be discussed.

Chemiluminescent spiroadamantane-1,2-dioxetanes: Recent advances in molecular imaging and biomarker detection.

Triggered chemiluminescence emission of spiroadamantane-1,2-dioxetanes to detect bioanalytes has fueled the emerging popularity of chemiluminescence imaging in live animals and cells. Recently, a structural evolution of the dioxetane scaffolds towards near-infrared emitters has been observed, and efforts have been made for quantitative and semi-quantitative detection of a wide range of analytes. In this review, we summarize the current chemiluminescence imaging developments of spiroadamantane-1,2-dioxetanes. Specifically, we look at examples which depict whole animal or cellular chemiluminescence imaging of small molecules and enzymes, as well as those that portray their potential diagnostic and therapeutic abilities, with an emphasis on analyte quantification and experimental parameters.

Dark Dynamic Therapy: Photosensitization without Light Excitation Using Chemiluminescence Resonance Energy Transfer in a Dioxetane-Erythrosin B Conjugate.

Reactive oxygen species (e.g., singlet oxygen) are the primary cytotoxic agents used in the clinically approved technique photodynamic therapy (PDT). Although singlet oxygen has high potential to effectively kill tumor cells, its production via light excitation of a photosensitizer has been limited by the penetration depth and delivery of light in tissue. To produce singlet oxygen without light excitation, we describe the use of Schaap's chemiluminescent scaffold comprising an adamantylidene-dioxetane motif. Functionalizing this scaffold with a photosensitizer, Erythrosin B, resulted in spontaneous chemiluminescence resonance energy transfer (CRET) leading to the production of singlet oxygen. We show that this compound is cell permeable and that the singlet oxygen produced via CRET is remarkably efficient in killing cancer cells at low micromolar concentrations. Moreover, we demonstrate that protection of the phenol on the chemiluminescent scaffold with a nitroreductase-responsive trigger group allows for cancer-selective dark dynamic cell death. Here, we present the concept of dark dynamic therapy using a small cell-permeable molecule capable of producing the effects of PDT in cells, without light.

Chemiluminescent 1,2-Dioxetane Iridium Complexes for Near-Infrared Oxygen Sensing.

Chemiluminescent iridium-based sensors which demonstrate oxygen dependent responses have been developed. The molecular probes, named IrCL-1, IrCL-2 and IrCL-3 consist of oxygen-sensitive iridium complexes attached to a spiroadamantane 1,2 dioxetane and operate via energy transfer from the chemiexcited benzoate to the corresponding iridium(III) complex. Complexing the iridium(III) center with π-extended ligands results in emission in the biologically relevant, near-infrared (NIR) region. All probes demonstrate varying oxygen tolerance, with IrCL-1 being the most oxygen sensitive. These probes have been further utilized for in vitro ratiometric imaging of oxygen, as well as for intraperitoneal, intramuscular and intratumoral imaging in live mice. To our knowledge, these are the first iridium-based chemiluminescent probes that have been employed for in vitro ratiometric oxygen sensing, and for in vivo tumor imaging.

Seeking Illumination: The Path to Chemiluminescent 1,2-Dioxetanes for Quantitative Measurements and In Vivo Imaging.

Chemiluminescence is a fascinating phenomenon that evolved in nature and has been harnessed by chemists in diverse ways to improve life. This Account tells the story of our research group's efforts to formulate and manifest spiroadamantane 1,2-dioxetanes with triggerable chemiluminescence for imaging and monitoring important reactive analytes in living cells, animals, and human clinical samples. Analytes like reactive sulfur, oxygen and nitrogen species, as well as pH and hypoxia can be indicators of cellular function or dysfunction and are often implicated in the causes and effects of disease. We begin with a foundation in binding-based and activity-based fluorescence imaging that has provided transformative tools for understanding biological systems. The intense light sources required for fluorescence excitation, however, introduce autofluorescence and light scattering that reduces sensitivity and complicates in vivo imaging. Our work and the work of our collaborators were the first to demonstrate that spiroadamantane 1,2-dioxetanes had sufficient brightness and biological compatibility for in vivo imaging of enzyme activity and reactive analytes like hydrogen sulfide (H2S) inside of living mice. This launched an era of renewed interest in 1,2-dioxetanes that has resulted in a plethora of new chemiluminescence imaging agents developed by groups around the world. Our own research group focused its efforts on reactive sulfur, oxygen, and nitrogen species, pH, and hypoxia, resulting in a large family of bright chemiluminescent 1,2-dioxetanes validated for cell monitoring and in vivo imaging. These chemiluminescent probes feature low background and high sensitivity that have been proven quite useful for studying signaling, for example, the generation of peroxynitrite (ONOO-) in cellular models of immune function and phagocytosis. This high sensitivity has also enabled real-time quantitative reporting of oxygen-dependent enzyme activity and hypoxia in living cells and tumor xenograft models. We reported some of the first ratiometric chemiluminescent 1,2-dioxetane systems for imaging pH and have introduced a powerful kinetics-based approach for quantification of reactive species like azanone (nitroxyl, HNO) and enzyme activity in living cells. These tools have been applied to untangle complex signaling pathways of peroxynitrite production in radiation therapy and as substrates in a split esterase system to provide an enzyme/substrate pair to rival luciferase/luciferin. Furthermore, we have pushed chemiluminescence toward commercialization and clinical translation by demonstrating the ability to monitor airway hydrogen peroxide in the exhaled breath of asthma patients using transiently produced chemiluminescent 1,2-dioxetanedione intermediates. This body of work shows the powerful possibilities that can emerge when working at the interface of light and chemistry, and we hope that it will inspire future scientists to seek out ever brighter and more illuminating ideas.

Computational and Experimental Investigations of the Fe2(µ-S2)/Fe2(µ-S)2 Equilibrium.

Density functional theory (DFT) calculations on Fe2S2(CO)6-2n(PMe3)2n for n = 0, 1, and 2 reveal that the most electron-rich derivatives (n = 2) exist as diferrous disulfides lacking an S-S bond. The thermal interconversion of the FeII2(S)2 and FeI2(S2) valence isomers is symmetry-forbidden. Related electron-rich diiron complexes [Fe2S2(CN)2(CO)4]2- of an uncertain structure are implicated in the biosynthesis of [FeFe]-hydrogenases. Several efforts to synthesize electron-rich derivatives of Fe2(µ-S2)(CO)6 (1) are described. First, salts of iron persulfido cyanides [Fe2(µ-S2)(CO)5(CN)]- and [Fe2(µ-S2)(CN)(CO)4(PPh3)]- were prepared by the reactions of NaN(tms)2 with 1 and Fe2(µ-S2)(CO)5(PPh3), respectively. Alternative approaches to electron-rich diiron disulfides targeted Fe2(µ-S2)(CO)4(diphosphine). Whereas the preparation of Fe2(µ-S2)(CO)4(dppbz) was straightforward, that of Fe2(µ-S2)(CO)4(dppv) required an indirect route involving the oxidation of Fe2(µ-SH)2(CO)4(dppv) (dppbz = C6H4-1,2-(PPh2)2, dppv = cis-C2H2(PPh2)2). DFT calculations indicate that the oxidation of Fe2(µ-SH)2(CO)4(dppv) produces singlet diferrous disulfide Fe2(µ-S)2(CO)4(dppv), which is sufficiently long-lived as to be trapped by ethylene. The reaction of 1 and dppv mainly afforded Fe2(µ-SCH=CHPPh2)(µ-SPPh2)(CO)5, implicating a S-centered reaction.

Revisiting Dinuclear Ruthenium Water Oxidation Catalysts: Effect of Bridging Ligand Architecture on Catalytic Activity.

An attractive catalytic pathway for the conversion of water to oxygen would involve two metal oxide centers combining in a constructive sense to make O═O. This prospect makes the study of certain dinuclear transition metal complexes particularly attractive. In this work, we describe the design and synthesis of two symmetrical bis-tridentate polypyridine ligands 6 and 12 that bind two RuII centers at a separation of 3.6 Šin 7 and 5.7 Šin 13. In the presence of CeIV at pH = 1, these systems oxidize water with the system having the more proximal metals being more reactive. In the case of the more proximal metal centers, the bridging ligand is a 3,6-disubstituted pyridazine which, under the influence of CeIV, cleaves into two [Ru(bpc)(pic)2CH3CN]+ fragments (14) which then function as the actual catalyst (bpc = 2,2'-bipyridine-6-carboxylate, pic = 4-methylpyridine). The second dinuclear catalyst contains a central pyrimidine ring which is less sensitive to oxidative decay and hence less reactive. Caution is advised in the use of CeIV as a sacrificial electron acceptor due to unexpected oxidative decay of the catalyst.

Redox and "Antioxidant" Properties of Fe2(µ-SH)2(CO)4(PPh3)2.

The chemistry of Fe2(µ-SH)2(CO)4(PPh3)2 (2HH) is described with attention to S-S coupling reactions. Produced by the reduction of Fe2(µ-S2)(CO)4(PPh3)2 (2), 2HH is an analogue of Fe2(µ-SH)2(CO)6 (1HH), which exhibits well-behaved S-centered redox. Both 2HH and the related 2MeH exist as isomers that differ with respect to the stereochemistry of the µ-SR ligands (R = H, Me). Compounds 2HH, 2MeH, and 2 protonate to give rare examples of Fe-SH and Fe-S2 hydrides. Salts of [H2]+, [H2HH]+, and [H2MeH]+ were characterized crystallographically. Complex 2HH reduces O2, H2O2, (PhCO2)2, and Ph2N2, giving 2. Related reactions involving 1HH gave uncharacterizable polymers. The differing behaviors of 2HH and 1HH reflect stabilization of the ferrous intermediates by the PPh3 ligands. When independently generated by the reaction of 2HH with 2,2,6,6-tetramethyl-1-piperidinyloxy, 2* quantitatively converts to 2 or, in the presence of C2H4, is trapped as the ethanedithiolate Fe2(µ-S2C2H4)(CO)4(PPh3)2. Evidence is presented that the Hieber-Gruber synthesis of 1 involves polysulfido intermediates [Fe2(µ-S n)2(CO)6]2- ( n > 1). Two relevant experiments are as follows: (i) protonation of [Fe4(µ-S)2(µ-S2)CO)12]2- gives 1 and 1HH, and (ii) oxidation of 1HH by sulfur gives 1.

Light-Driven Hydrogen Generation from Microemulsions Using Metallosurfactant Catalysts and Oxalic Acid.

A unique microemulsion-based photocatalytic water reduction system is demonstrated. Iridium- and rhodium-based metallosurfactants, namely, [Ir(ppy)2(dhpdbpy)]Cl and [Rh(dhpdbpy)2Cl2]Cl (where ppy = 2-phenylpyridine and dhpdbpy = 4,4'-diheptadecyl-2,2'-bipyridine), were employed as photosensitizer and proton reducing catalyst, respectively, along with oxalic acid as a sacrificial reductant in a toluene/water biphasic mixture. The addition of 1-octylamine is proposed to initiate the reaction, by coupling with oxalic acid to form an ion pair, which acts as an additional surfactant. Concentration optimizations yielded high activity for both the photosensitizer (240 turnovers, turnover frequency (TOF) = 200 h-1) and catalyst (400 turnovers, TOF = 230 h-1), with the system generating hydrogen even after 95 h. Mechanistic insights were provided by gas-phase Raman, electrochemical, and luminescence quenching analysis, suggesting oxidative quenching to be the principle reaction pathway.

Cyano-decorated ligands: a powerful alternative to fluorination for tuning the photochemical properties of cyclometalated Ir(iii) complexes.

A new cyclometalating ligand, featuring nitrile moieties to enhance the photophysical and consequently photocatalytic properties of bis-cyclometalated Ir(iii) complexes, was synthesized. Nitrile moieties were selected to replace expensive and environmentally problematic fluoride moieties commonly employed for synthetic tuning of chromophores. Two new chromophores bearing the new nitrile-decorated ligand were synthesized with strong electron-donating and electron-withdrawing ancillary ligands to probe extremes of the complexes' tunability. These complexes possessed rich and drastically different electrochemical and photophysical properties. One chromophore possessed a particularly long lifetime of approximately 8 µs; it was also a remarkably efficient triplet emitter with a quantum yield of 63%. The complexes were finally assessed as photosensitizers of water reduction with Pt colloids, where both complexes produced hydrogen with optimized conditions reaching 2000 and 1400 turnovers.

Electron-Poor Thiophene 1,1-Dioxides: Synthesis, Characterization, and Application as Electron Relays in Photocatalytic Hydrogen Generation.

The synthesis and characterization of electron-poor thiophene 1,1-dioxides bearing cyanated phenyl groups are reported. The electron-accepting nature of these compounds was evaluated by cyclic voltammetry, and highly reversible and facile reductions were observed for several derivatives. Moreover, some of the reduced thiophene dioxides form colorful anions, which were investigated spectroelectrochemically. Photoluminescence spectra of the electron-deficient sulfones were measured in CH2 Cl2, and they emit in the blue-green region with significant variation in the quantum yield depending on the aryl substituents. By expanding the degree of substitution on the phenyl rings, quantum yields up to 34 % were obtained. X-ray diffraction data are reported for two of the thiophene 1,1-dioxides, and the electronic structure was probed for all synthesized derivatives through DFT calculations. The dioxides were also examined as electron relays in a photocatalytic water reduction reaction, and they showed potential to boost the efficiency.

Mechanistic Insight into the Dehydro-Diels-Alder Reaction of Styrene-Ynes.

The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene-ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene-ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.

[Ir(N

The relatively unexplored luminophore architecture [Ir(N^N^N)(C^N)L](+) (N^N^N = tridentate polypyridyl ligand, C^N = 2-phenylpyridine derivative, and L = monodentate anionic ligand) offers the stability of tridentate polypyridyl coordination along with the tunability of three independently variable ligands. Here, a new family of these luminophores has been prepared based on the previously reported compound [Ir(tpy)(ppy)Cl](+) (tpy = 2,2':6',2″-terpyridine and ppy = 2-phenylpyridine). Complexes are obtained as single stereoisomers, and ligand geometry is unambiguously assigned via X-ray crystallography. Electrochemical analysis of the materials reveals facile HOMO modulation through ppy functionalization and alteration of the monodentate ligand's field strength. Emission reflects similar modulation shifting from orange to greenish-blue upon replacement of chloride with cyanide. Many of the new compounds exhibit impressive room temperature phosphorescence with lifetimes near 3 µs and quantum yields reaching 28.6%. Application of the new luminophores as photosensitizers for photocatalytic hydrogen generation reveals that their photostability in coordinating solvent is enhanced as compared to popular [Ir(ppy)2(bpy)](+) (bpy = 2,2'-bipyridine) photosensitizers. Yet, the binding of their monodentate ligand emerges as a source of instability during the redox processes of cyclic voltammetry and mass spectrometry. DFT modeling of electronic structure is provided for all compounds to elucidate experimental properties.

Photocatalytic hydrogen generation system using a nickel-thiolate hexameric cluster.

We report the use of a nickel-thiolate hexameric cluster, Ni6(SC2H4Ph)12, for photocatalytic hydrogen production from water. The nickel cluster was synthesized ex-situ and characterized by various techniques. Single crystal X-ray analysis, (1)H NMR, 2D COSY, ESI-MS, UV-visible spectroscopy, and TGA provided insight into the structure and confirmed the purity and stability of the cluster. Cyclic voltammetry helped confirm hydrogen evolution reaction (HER) activity of this catalyst. Photoreactions carried out using an iridium photosensitizer, Ir(F-mppy)2(dtbbpy)[PF6], and TEA as the sacrificial reductant revealed the high activity of the Ni6 cluster as a water reducing catalyst. High TONs (3750) and TOFs (970 h(-1)) were obtained at optimum catalyst concentration (0.025 mM), with low concentrations of catalyst yielding up to 30,000 turnovers. Quenching studies, along with the evidence obtained from the electrochemical analysis, showed that this water reduction system proceeds through a reductive quenching mechanism. Mercury poisoning studies confirmed that no active, metallic colloids were formed during the photocatalytic reaction.

Ex-situ dispersion of core-shell nanoparticles of Cu-Pt on an in situ modified carbon surface and their enhanced electrocatalytic activities.

Direct dispersion of core-shell nanoparticles on a carbon support (Cu@Pt/C) has been achieved while retaining the essential core-shell features of the nanoparticles by adopting an in situ surface modification-cum-anchoring strategy.