Synthesis, Characterization, and Reactivity of a Synthetic End-On Cobalt(II) Alkyl Persulfide Complex as a Model Platform for Thiolate Persulfidation.

Persulfides (RSS-) are ubiquitous source of sulfides (S2-) in biology, and interactions between RSS- and bioinorganic metal centers play critical roles in biological hydrogen sulfide (H2S) biogenesis, signaling, and catabolism. Here, we report the use of contact-ion stabilized [Na(15-crown-5)][tBuSS] (1) as a simple synthon to access rare metal alkyl persulfide complexes and to investigate the reactivity of RSS- with transition metal centers to provide insights into metal thiolate persulfidation, including the fundamental difference between alkyl persulfides and alkyl thiolates. Reaction of 1 with [CoII(TPA)(OTf)]+ afforded the η1-alkyl persulfide complex [CoII(TPA)(SStBu)]+ (2), which was characterized by X-ray crystallography, UV-vis spectroscopy, and Raman spectroscopy. RSS- coordination to the Lewis acidic Co2+ center provided additional stability to the S-S bond, as evidenced by a significant increase in the Raman stretching frequency for 2 (vS-S = 522 cm-1, ΔvS-S = 66 cm-1). The effect of persulfidation on metal center redox potentials was further elucidated using cyclic voltammetry, in which the Co2+ → Co3+ oxidation potential of 2 (Ep,a = +89 mV vs SCE) is lowered by nearly 700 mV when compared to the corresponding thiolate complex [CoII(TPA)(StBu)]+ (3) (Ep,a = +818 mV vs SCE), despite persulfidation being generally seen as an oxidative post-translational modification. The reactivity of 2 toward reducing agents including PPh3, BH4-, and biologically relevant thiol reductant DTT led to different S2- output pathways, including formation of a dinuclear 2Co-2SH complex [CoII2(TPA)2(µ2-SH)2]2+(4).

Carbon Dioxide Capture by Niobium Polyoxometalate Fragmentation.

High oxidation state metal cations in the form of oxides, oxoanions, or oxoperoxoanions have diverse roles in carbon dioxide removal (direct air capture and point source). Features include providing basic oxygens for chemisorption reactions, direct binding of carbonate, and catalyzing low-temperature CO2 release to regenerate capture media. Moreover, metal oxides and aqueous metal-oxo species are stable in harsh, point-source conditions. Here, we demonstrate aqueous niobium polyoxometalate (POM) carbon capture ability, specifically [Nb6O19]8-, Nb6. Upon exposure of aqueous Nb6 to CO2, Nb6 fragments and binds chemisorbed carbonate, evidenced by crystallization of Nb-carbonate POMs including [Nb22O53(CO3)16]28-and [Nb10O25(CO3)6]12-. While Rb/Cs+ counter cations yield crystal structures to understand the chemisorption processes, K+ counter cations enable higher capture efficiency (based on CO3/Nb ratio), determined by CHN analysis and thermogravimetry-mass spectrometry of the isolated solids. Sum frequency generation spectroscopy also showed higher carbon capture efficiency of the K-Nb6 solutions at the air-water interface, while small-angle X-ray scattering (SAXS) provided insights into the role of the alkalis in influencing these processes. Tetramethylammonium counter cations, like K+, demonstrate high efficiency of carbonate chemisorption at the interface, but SAXS and Raman of the bulk showed a predominance of a Nb24-POM (HxNb24O72, x ∼ 9) that does not bind carbonate. Control experiments show that carbonate detected at the interface is Nb-bound, and the Nb-carbonate species are stabilized by alkalis, demonstrating their supporting role in aqueous Nb-POM CO2 chemisorption. Of fundamental importance, this study presents rare examples of directing POM speciation with a gas, instead of liquid phase acid or base.

Synthesis and Properties of Fluorenone-Containing Cycloparaphenylenes and Their Late-Stage Transformation.

Cycloparaphenylenes (CPPs) are the smallest possible armchair carbon nanotubes, the properties of which strongly depend on their ring size. They can be further tuned by either peripheral functionalization or by replacing phenylene rings for other aromatic units. Here we show how four novel donor-acceptor chromophores were obtained by incorporating fluorenone or 2-(9H-fluoren-9-ylidene)malononitrile into the loops of two differently sized CPPs. Synthetically, we managed to perform late-stage functionalization of the fluorenone-based rings by high-yielding Knoevenagel condensations. The structures were confirmed by X-ray crystallographic analyses, which revealed that replacing a phenylene for a fused-ring-system acceptor introduces additional strain. The donor-acceptor characters of the CPPs were supported by absorption and fluorescence spectroscopic studies, electrochemical studies (displaying the CPPs as multi-redox systems undergoing reversible or quasi-reversible redox events), as well as by computations. The oligophenylene parts were found to comprise the electron donor units of the macrocycles and the fluorenone parts the acceptor units.

Reversible Hydrosulfide (HS-) Binding Using Exclusively C-H Hydrogen-Bonding Interactions in Imidazolium Hosts.

H2S is a physiologically important signaling molecule with complex roles in biology and exists primarily as HS- at physiological pH. Despite this anionic character, few investigations have focused on the molecular recognition and reversible binding of this important biological anion. Using a series of imidazole and imidazolium host molecules, we investigate the role of preorganization and charge on HS- binding. Using a macrocyclic bis-imidazolium receptor, we demonstrate the unexpected 2:1 host-guest binding of HS-, which was characterized both in solution and by X-ray crystallography. To the best of our knowledge, this is the first example of this binding stoichiometry for HS- binding. Moreover, the short C-H···S distances of 2.53, 2.54, 2.76, and 2.79 Å are well within the sum of the van der Waals radii of the interacting atoms, which is consistent with strong C-H···S interactions.

A High-Yielding Active Template Click Reaction (AT-CuAAC) for the Synthesis of Mechanically Interlocked Nanohoops.

Mechanically interlocked molecules (MIMs) represent an exciting yet underexplored area of research in the context of carbon nanoscience. Recently, work from our group and others has shown that small carbon nanotube fragments-[n]cycloparaphenylenes ([n]CPPs) and related nanohoop macrocycles-may be integrated into mechanically interlocked architectures by leveraging supramolecular interactions, covalent tethers, or metal-ion templates. Still, available synthetic methods are typically difficult and low yielding, and general methods that allow for the creation of a wide variety of these structures are limited. Here we report an efficient route to interlocked nanohoop structures via the active template Cu-catalyzed azide-alkyne cycloaddition (AT-CuAAC) reaction. With the appropriate choice of substituents, a macrocyclic precursor to 2,2'-bipyridyl embedded [9]CPP (bipy[9]CPP) participates in the AT-CuAAC reaction to provide [2]rotaxanes in near-quantitative yield, which can then be converted into the fully π-conjugated catenane structures. Through this approach, two nanohoop[2]catenanes are synthesized which consist of a bipy[9]CPP catenated with either Tz[10]CPP or Tz[12]CPP (where Tz denotes a 1,2,3-triazole moiety replacing one phenylene ring in the [n]CPP backbone).

Taming the Dichalcogenides: Isolation, Characterization, and Reactivity of Elusive Perselenide, Persulfide, Thioselenide, and Selenosulfide Anions.

Reactive sulfur species (RSS) and reactive selenium species (RSeS) play integral roles in hydrogen sulfide (H2S) and hydrogen selenide (H2Se) biological signaling pathways, and dichalcogenide anions are proposed transient intermediates that facilitate a variety of biochemical transformations. Herein we report the selective synthesis, isolation, spectroscopic and structural characterization, and fundamental reactivity of persulfide (RSS-), perselenide (RSeSe-), thioselenide (RSSe-), and selenosulfide (RSeS-) anions. The isolated chalcogenides do not rely on steric protection for stability and have steric profiles analogous to cysteine (Cys). Simple reduction of S8 or Se by potassium benzyl thiolate (KSBn) or selenolate (KSeBn) in the presence of 18-crown-6 afforded [K(18-crown-6)][BnSS] (1), [K(18-crown-6)][BnSeSe] (2), [K(18-crown-6][BnSSe] (3), and [K(18-crown-6][BnSeS] (4). The chemical structure of each dichalcogenide was confirmed by X-ray crystallography and solution-state 1H, 13C, and 77Se NMR spectroscopy. To advance our understanding of the reactivity of these species, we demonstrated that reduction of 1-4 by PPh3 readily generates E═PPh3 (E: S, Se), and reduction of 1, 3, and 4 by DTT readily produces HE-/H2E. Furthermore, 1-4 react with CN- to produce ECN-, which is consistent with the detoxifying effects of dichalcogenide intermediates in the Rhodanese enzyme. Taken together, this work provides new insights into the inherent structural and reactivity characteristics of dichalcogenides relevant to biology and advances our understanding of the fundamental properties of these reactive anions.

Comparison of Antiaromatic Properties in a Series of Structurally Isomeric Naphthothiophene-Fused s-Indacenes.

Fusion of aromatic subunits to stabilize an antiaromatic core allows the isolation and study of otherwise unstable paratropic systems. A complete study of a series of six naphthothiophene-fused s-indacene isomers is herein described. Additionally, the structural modifications resulted in increased π-π overlap in the solid state, which was further explored through changing the sterically blocking mesityl group to (triisopropylsilyl)ethynyl in three derivatives. The computed antiaromaticity of the six isomers is compared to the observed physical properties, such as NMR chemical shift, UV-vis, and CV data. We find that the calculations predict the most antiaromatic isomer and give a general estimation of the relative degree of paratropicity for the remaining isomers, when compared to the experimental results.

Impact of Internal Charge Transfer on the Photophysical Properties of Pyridine-Fused Phosphorus-Nitrogen Heterocycles.

The phosphaquinolinone scaffold has been previously studied as a modular core for a variety of fluorescent species where use of substituent effects has focused on increasing or decreasing electron density in the core rings. We now report the synthesis and analysis of several pyridine-containing phosphaquinolinone species exhibiting notable linear conjugation from the aryl-substituent to electron-withdrawing pyridyl nitrogen. Varying the nature of the aryl substituent from electron-withdrawing to electron-donating leads to the generation of an internal charge-transfer (ICT) band in the absorbance spectrum, which becomes the dominant absorbance in terms of intensity in the most electron-rich -NMe2 example. This heterocycle exhibits improved photophysical properties compared to others in the set including high quantum yield and considerably red-shifted emission. The enhanced ICT can be observed in the X-ray data where a rare example of molecule co-planarity is observed. Computational data show increased localization of negative charge on the pyridyl nitrogen as the electron-donating character of the aryl-substituent increases.

Tunable Macrocyclic Polyparaphenylene Nanolassos via Copper-Free Click Chemistry.

Deriving diverse compound libraries from a single substrate in high yields remains to be a challenge in cycloparaphenylene chemistry. In here, a strategy for the late-stage functionalization of shape-persistent alkyne-containing cycloparaphenylene has been explored using readily available azides. The copper-free [3+2]azide-alkyne cycloaddition provided high yields (>90 %) in a single reaction step. Systematic variation of the azides from electron-rich to -deficient shines light on how peripheral substitution influences the characteristics of the resulting adducts. We find that among the most affected properties are the molecular shape, the oxidation potential, excited state features, and affinities towards different fullerenes. Joint experimental and theoretical results are presented including calculations with the state-of-the-art, artificial intelligence-enhanced quantum mechanical method 1 (AIQM1).

2-λ5-Phosphaquinolin-2-ones as Non-cytotoxic, Targetable, and pH-Stable Fluorophores.

Several phosphaquinolinone derivatives have been synthesized and characterized to explore their usefulness in the realm of cell imaging. Solution-state photophysical properties in both aqueous and organic solutions were collected for these derivatives. Additionally, CCK-8 cell viability assays and fluorescent imaging in HeLa cells incubated with the new heterocyclic derivatives show evidence of favorable cell permeability, cell viability, and moderate intracellular localization when appended with the well-known morpholine targeting motif.

Supramolecular Activation of S8 by Cucurbiturils in Water and Mechanism of Reduction to H2S by Thiols: Insights into Biological Sulfane Sulfur Trafficking.

Reactive sulfur species (RSS) play critical roles in diverse chemical environments. Molecules containing sulfane sulfur (S0) have emerged as key species involved in cellular redox buffering as well as RSS generation, translocation, and action. Using cucurbit[7]uril (CB[7]) as a model hydrophobic host, we demonstrate here that S8 can be encapsulated to form a 1:1 host guest complex, which was confirmed by solution state experiments, mass spectrometry, and X-ray crystallography. The solid state structure of CB[7]/S8 shows that the encapsulated S8 is available to nucleophiles through the carbonyl portals of the host. Treatment of CB[7]/S8 with thiols results in efficient reduction of S8 to H2S in water at physiological pH. We establish that encapsulated S8 is attacked by a thiol within the CB[7] host and that the resultant soluble hydropolysulfide is ejected into solution, where it reacts further with thiols to generate soluble sulfane sulfur carriers and ultimately H2S. The formation of these intermediate is supported by observed kinetic saturation behavior, competitive inhibition experiments, and alkylative trapping experiments. We also demonstrate that CB[7]/S8 can be used to increase sulfane sulfur levels in live cells using fluorescence microscopy. More broadly, this work suggests a general activation mechanism of S8 by hydrophobic motifs, which may be applicable to proteins, membranes, or other bimolecular compartments that could transiently bind and solubilize S8 to promote reaction with thiols to solubilize and shuttle S8 back into the redox labile sulfane sulfur pool. Such a mechanism would provide an attractive manifold in which to understand the RSS translocation and trafficking.

Controlling Tautomerization in Pyridine-Fused Phosphorus-Nitrogen Heterocycles.

Inclusion of a second nitrogen atom in the aromatic core of phosphorus-nitrogen (PN) heterocycles results in unexpected tautomerization to a nonaromatic form. This tautomerization, initially observed in the solid state through X-ray crystallography, is also explained by computational analysis. We prepared an electron deficient analogue (2 e) with a fluorine on the pyridine ring and showed that the weakly basic pyridine resisted tautomerization, providing key insights to why the transformation occurs. To study the difference in solution vs. solid-state heterocycles, alkylated analogues that lock in the quinoidal tautomer were synthesized and their different 1 H NMR and UV/Vis spectra studied. Ultimately, we determined that all heterocycles are the aromatic tautomer in solution and all but 2 e switch to the quinoidal tautomer in the solid state. Better understanding of this transformation and under what circumstances it occurs suggest future use in a switchable on/off hydrogen-bond-directed receptor that can be tuned for complementary hydrogen bonding.

Thionitrite (SNO- ) and Perthionitrite (SSNO- ) are Simple Synthons for Nitrosylated Iron Sulfur Clusters.

S/N crosstalk species derived from the interconnected reactivity of H2 S and NO facilitate the transport of reactive sulfur and nitrogen species in signaling, transport, and regulatory processes. We report here that simple Fe2+ ions, such as those that are bioavailable in the labile iron pool (LIP), react with thionitrite (SNO- ) and perthionitrite (SSNO- ) to yield the dinitrosyl iron complex [Fe(NO)2 (S5 )]- . In the reaction of FeCl2 with SNO- we were able to isolate the unstable intermediate hydrosulfido mononitrosyl iron complex [FeCl2 (NO)(SH)]- , which was characterized by X-ray crystallography. We also show that [Fe(NO)2 (S5 )]- is a simple synthon for nitrosylated Fe-S clusters via its reduction with PPh3 to yield Roussin's Red Salt ([Fe2 S2 (NO)4 ]2- ), which highlights the role of S/N crosstalk species in the assembly of fundamental Fe-S motifs.

Hydrolysis-Based Small-Molecule Hydrogen Selenide (H2Se) Donors for Intracellular H2Se Delivery.

Hydrogen selenide (H2Se) is a central metabolite in the biological processing of selenium for incorporation into selenoproteins, which play crucial antioxidant roles in biological systems. Despite being integral to proper physiological function, this reactive selenium species (RSeS) has received limited attention. We recently reported an early example of a H2Se donor (TDN1042) that exhibited slow, sustained release through hydrolysis. Here we expand that technology based on the P═Se motif to develop cyclic-PSe compounds with increased rates of hydrolysis and function through well-defined mechanisms as monitored by 31P and 77Se NMR spectroscopy. In addition, we report a colorimetric method based on the reaction of H2Se with NBD-Cl to generate NBD-SeH (λmax = 551 nm), which can be used to detect free H2Se. Furthermore, we use TOF-SIMS (time of flight secondary ion mass spectroscopy) to demonstrate that these H2Se donors are cell permeable and use this technique for spatial mapping of the intracellular Se content after H2Se delivery. Moreover, these H2Se donors reduce endogenous intracellular reactive oxygen species (ROS) levels. Taken together, this work expands the toolbox of H2Se donor technology and sets the stage for future work focused on the biological activity and beneficial applications of H2Se and related bioinorganic RSeS.

Total Synthesis of Chalaniline B: An Antibiotic Aminoxanthone from Vorinostat-Treated Fungus Chalara sp. 6661.

Chalaniline B [1-anilino-2,8-dihydroxy-3-(hydroxymethyl)xanthone], an antibiotic previously isolated from vorinostat-treated Chalara sp., was prepared in 7 steps from 2-hydroxyxanthone by a route incorporating regioselective oxidative transformations (bromination at C1/C3, ketone directed Pd(II)-catalyzed hydroxylation at C8), installation of the C1-anilino moiety by a regioselective Buchwald-Hartwig amination reaction from 1,3-dibromo-2,8-dimethoxyxanthone, and late-stage hydroxymethylation at C3 using a Stille cross-coupling. Biological evaluation of deshydroxymethylchalaniline B (1-anilino-2,8-dihydroxyxanthone) revealed MIC values of 8 µg mL-1 (25 µM) against both methicillin resistant S. aureus and B. subtilis.

NO Coupling by Nonclassical Dinuclear Dinitrosyliron Complexes to Form N2O Dictated by Hemilability.

Selective coupling of NO by a nonclassical dinuclear dinitrosyliron complex (D-DNIC) to form N2O is reported. The coupling is facilitated by the pyridinediimine (PDI) ligand scaffold, which enables the necessary denticity changes to produce mixed-valent, electron-deficient tethered DNICs. One-electron oxidation of the [{Fe(NO)2}]210/10 complex Fe2(PyrrPDI)(NO)4 (4) results in NO coupling to form N2O via the mixed-valent {[Fe(NO)2]2}9/10 species, which possesses an electron-deficient four-coordinate {Fe(NO)2}10 site, crucial in N-N bond formation. The hemilability of the PDI scaffold dictates the selectivity in N-N bond formation because stabilization of the five-coordinate {Fe(NO)2}9 site in the mixed-valent [{Fe(NO)2}]29/10 species, [Fe2(Pyr2PDI)(NO)4][PF6] (6), does not result in an electron-deficient, four-coordinate {Fe(NO)2}10 site, and hence no N-N coupling is observed.

Biodiversity, Bioactivity, and Metabolites of High Desert Derived Oregonian Soil Bacteria.

From arid, high desert soil samples collected near Bend, Oregon, 19 unique bacteria were isolated. Each strain was identified by 16S rRNA gene sequencing, and their organic extracts were tested for antibacterial and antiproliferative activities. Noteworthy, six extracts (30 %) exhibited strong inhibition resulting in less than 50 % cell proliferation in more than one cancer cell model, tested at 10 µg/mL. Principal component analysis (PCA) of LC/MS data revealed drastic differences in the metabolic profiles found in the organic extracts of these soil bacteria. In total, fourteen potent antibacterial and/or cytotoxic metabolites were isolated via bioactivity-guided fractionation, including two new natural products: a pyrazinone containing tetrapeptide and 7-methoxy-2,3-dimethyl-4H-chromen-4-one, as well as twelve known compounds: furanonaphthoquinone I, bafilomycin C1 and D, FD-594, oligomycin A, chloramphenicol, MY12-62A, rac-sclerone, isosclerone, tunicamycin VII, tunicamycin VIII, and (6S,16S)-anthrabenzoxocinone 1.264-C.

A Tale of Two Isomers: Enhanced Antiaromaticity/Diradical Character versus Deleterious Ring-Opening of Benzofuran-fused s-Indacenes and Dicyclopenta[b,g]naphthalenes.

We examine the effects of fusing two benzofurans to s-indacene (indacenodibenzofurans, IDBFs) and dicyclopenta[b,g]naphthalene (indenoindenodibenzofurans, IIDBFs) to control the strong antiaromaticity and diradical character of these core units. Synthesis via 3-functionalized benzofuran yields syn-IDBF and syn-IIDBF. syn-IDBF possesses a high degree of paratropicity, exceeding that of the parent hydrocarbon, which in turn results in strong diradical character for syn-IIDBF. In the case of the anti-isomers, synthesized via 2-substituted benzofurans, these effects are decreased; however, both derivatives undergo an unexpected ring-opening reaction during the final dearomatization step. All the results are compared to the benzothiophene-fused analogues and show that the increased electronegativity of oxygen in the syn-fused derivatives leads to enhancement of the antiaromatic core causing greater paratropicity. For syn-IIDBF increased diradical character results from rearomati-zation of the core naphthalene unit in order to relieve this paratropicity.

Exploration of the Solid-State Sorption Properties of Shape-Persistent Macrocyclic Nanocarbons as Bulk Materials and Small Aggregates.

Porous molecular materials combine benefits such as convenient processability and the possibility for atom-precise structural fine-tuning which makes them remarkable candidates for specialty applications in the areas of gas separation, catalysis, and sensing. In order to realize the full potential of these materials and guide future molecular design, knowledge of the transition from molecular properties into materials behavior is essential. In this work, the class of compounds termed cycloparaphenylenes (CPPs)-shape-persistent macrocycles with built-in cavities and radially oriented π-systems-was selected as a conceptually simple class of intrinsically porous nanocarbons to serve as a platform for studying the transition from analyte sorption properties of small aggregates to those of bulk materials. In our detailed investigation, two series of CPPs were probed: previously reported hoop-shaped [n]CPPs and a novel family of all-phenylene figure-8 shaped (lemniscal) bismacrocycles, termed spiro[n,n]CPPs. A series of nanocarbons with different macrocycle sizes and heteroatom content have been prepared by atom-precise organic synthetic methods, and their structural, photophysical, and electronic attributes were disclosed. Detailed experimental studies (X-ray crystallography, gas sorption, and quartz-crystal microbalance measurements) and quantum chemical calculations provided ample evidence for the importance of the solid-state arrangement on the porosity and analyte uptake ability of intrinsically porous molecular nanocarbons. We demonstrate that this molecular design principle, i.e., incorporation of sterically demanding spiro junctions into the backbone of nanohoops, enables the manipulation of solid-state morphology without significantly changing the nature and size of the macrocyclic cavities. As a result, the novel spiro[n,n]CPPs showed a remarkable performance as high affinity material for vapor analyte sensing.

Molecule Isomerism Modulates the Diradical Properties of Stable Singlet Diradicaloids.

Inclusion of quinoidal cores in conjugated hydrocarbons is a common strategy to modulate the properties of diradicaloids formed by aromaticity recovery within the quinoidal unit. Here we describe an alternative approach of tuning of diradical properties in indenoindenodibenzothiophenes upon anti → syn isomerism of the benzothiophene motif. This alters the relationship of the S atom with the radical center from linear to cross conjugation yet retains the same 2,6-naphtho conjugation pattern of the rearomatized core. We conduct a full comparison between the anti and syn derivatives based on structural, spectroscopic, theoretical, and magnetic measurements, showing that these systems are stable open-shell singlet diradicaloids that only access their triplet state at elevated temperatures.