Probing the Antiaromaticity and Coordination Chemistry of Bowl-Shaped Zinc(II) Norcorrole.

Zinc norcorrole was prepared as its pyridine complex (ZnNc·pyridine) by metalation of freebase norcorrole. The ZnNc·pyridine complex is distinctly bowl-shaped, as demonstrated by both X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopy showed characteristic ring current deshielding effects, with different magnitudes on either face of the bowl-shaped complex. Exchanging the pyridine ligand with the bidentate ligand DABCO results in the formation of a stable (ZnNc)2·DABCO sandwich complex, which was also characterized by crystallography and NMR spectroscopy. The NMR resonances of the axial ligands in all of the complexes demonstrate that the paratropic ring current in zinc norcorrole is approximately 40 nA/T, which is comparable in magnitude to the diatropic ring current in porphyrin. Analysis of the ligand-exchange processes on addition of DABCO to ZnNc·pyridine showed that ZnNc coordinates to axial nitrogen-containing ligands with approximately 1000-fold higher binding constants than analogous zinc porphyrins.

The influence of backbone fluorination on the helicity of α/γ-hybrid peptides.

Peptides that are composed of an alternating pattern of α- and γ-amino acids are potentially valuable as metabolism-resistant bioactive agents. For optimal function, some kind of conformational restriction is usually required to either stabilize the dominant 12-helix, or else to divert the peptide away from this conformation in a controlled way. Herein, we explore stereoselective fluorination as a method for controlling the conformations of α/γ-hybrid peptides. We show through a combination of X-ray, NMR and CD analyses that fluorination can either stabilize or disrupt the 12-helix, depending on the fluorine stereochemistry. These findings could inform the ongoing development of diverse functional hybrid peptides.

Spin Crossover Induced by Changing the Identity of the Secondary Metal Ion from PdII to NiII in a Face-Centered FeII 8 MII 6 Cubic Cage.

Discrete spin crossover (SCO) heteronuclear cages are a rare class of materials which have potential use in next-generation molecular transport and catalysis. Previous investigations of cubic cage [Fe8 Pd6 L8 ]28+ constructed using semi-rigid metalloligands, found that FeII centers of the cage did not undergo spin transition. In this work, substitution of the secondary metal center at the face of the cage resulted in SCO behavior, evidenced by magnetic susceptibility, Mössbauer spectroscopy and single crystal X-ray diffraction. Structural comparisons of these two cages shed light on the possible interplay of inter- and intramolecular interactions associated with SCO in the NiII analogue, 1 ([Fe8 Ni6 L8 (CH3 CN)12 ]28+ ). The distorted octahedral coordination environment, as well as the occupation of the CH3 CN in the NiII axial positions of 1, prevented close packing of cages observed in the PdII analogue. This led to offset, distant packing arrangements whereby important areas within the cage underwent dramatic structural changes with the exhibition of SCO.

Ruthenium(II) Complexes of a Xanthene-Spanned Dicarbene Ligand.

Octahedral ruthenium(II) complexes of a xanthene-di(N-heterocyclic carbene) ancillary ligand (XdC) have been prepared and structurally characterized. Examples catalyze the transfer hydrogenation of ketones {[Ru(CO)I2(C,O,C'-XdC)] (1) and [Ru(CO)(MeCN)2(C,O,C'-XdC)]2+ (22+)} and the selective electrochemical reduction of CO2 to CO {[Ru(N,N'-bpy)(CO)(C,O,C'-XdC)]2+ (32+) at 0.40 V overpotential in MeCN-H2O (1 M)}. The reaction of 1 with KBEt3H afforded isomers of [(C,C'-XdC)Ru(µ-H)(H)]2 dimers, which are stable to reductive elimination of the XdC ligand, thereby suggesting similar (XdC)Rh(coligand)(H)x species may be viable intermediates in catalyses. The electrochemical reduction of CO2 involves a double reduction of 32+ to 3••, which has been characterized by IR-SEC and DFT calculations. The DFT calculations suggest the Ru-Oxanth bond breaks in 3••, opening a metal site for CO2 binding with selectivity over protons enabled by the diffuse nature of the HOMO delocalized over the metal and the bipyridine and carbonyl coligands. The results point to the promise of metal complexes of flexible and hemilabile xanthene-(NHC)2 ancillary ligands in catalysis.

Pyrimido[1,2-a]benzimidazoles as inhibitors of oncoproteins ubiquitin specific protease 5 and MYCN in the childhood cancer neuroblastoma.

The MYCN oncogene and histone deacetylases (HDACs) are key driver genes in the childhood cancer, neuroblastoma. We recently described a novel pyridobenzimidazole analogue, SE486-11, which enhanced the therapeutic effectiveness of HDAC inhibitors by increasing MYCN ubiquitination through effects on the deubiquitinase, ubiquitin-specific protease 5 (USP5). Here we describe the synthesis of a novel series of pyrimido[1,2-a]benzimidazole derivatives, and an evaluation of their cytopathic effects against non-malignant and human neuroblastoma cell lines. Among the tested analogues, 4-(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine (3a) was the most active compound against neuroblastoma cells (IC50 ≤ 2 µM), with low cytotoxicity (IC50 ≥ 15 µM) to normal cells. We show compound 3a bound to USP5 protein (Kd = 0.47 µM) in vitro and synergistically enhanced the efficacy of HDAC inhibitors against neuroblastoma cells. Moreover, knockdown of USP5 and MYCN in treated neuroblastoma cells showed that both USP5 and MYCN expression was necessary for the cytopathic activity of compound 3a, thus providing a clinically relevant rationale for further development of this of pyrimido[1,2-a]benzimidazole.

Anomalous Structural Evolution and Glassy Lattice in Mixed-Halide Hybrid Perovskites.

Hybrid halide perovskites have emerged as highly promising photovoltaic materials because of their exceptional optoelectronic properties, which are often optimized via compositional engineering like mixing halides. It is well established that hybrid perovskites undergo a series of structural phase transitions as temperature varies. In this work, the authors find that phase transitions are substantially suppressed in mixed-halide hybrid perovskite single crystals of MAPbI3-x Brx (MA = CH3 NH3 + and x = 1 or 2) using a complementary suite of diffraction and spectroscopic techniques. Furthermore, as a general behavior, multiple crystallographic phases coexist in mixed-halide perovskites over a wide temperature range, and a slightly distorted monoclinic phase, hitherto unreported for hybrid perovskites, is dominant at temperatures above 100 K. The anomalous structural evolution is correlated with the glassy behavior of organic cations and optical phonons in mixed-halide perovskites. This work demonstrates the complex interplay between composition engineering and lattice dynamics in hybrid perovskites, shedding new light on their unique properties.

Efficient Reductive Defluorination of Branched PFOS by Metal-Porphyrin Complexes.

Vitamin B12 (VB12) has been reported to degrade PFOS in the presence of TiIII citrate at 70 °C. Porphyrin-based catalysts have emerged as VB12 analogues and have been successfully used in various fields of research due to their interesting structural and electronic properties. However, there is inadequate information on the use of these porphyrin-based metal complexes in the defluorination of PFOS. We have therefore explored a series of porphyrin-based metal complexes for the degradation of PFOS. CoII-5,10,15,20-tetraphenyl-21H,23H-porphyrin (CoII-TPP), CoII-5,10,15,20-tetrakis(4-methoxyphenyl)-21H,23H-porphyrin (CoII-M-TPP), and CoIII-M-TPP exhibited efficient reductive defluorination of the branched PFOS. Within 5-8 h, these compounds achieved the same level of PFOS defluorination as VB12 achieved in 7-10 days. For branched isomers, the specific removal rate of the CoII-TPP-TiIII citrate system is 64-105 times higher than that for VB12-TiIII citrate. Moreover, the CoII-TPP-TiIII citrate system displayed efficient (51%) defluorination for the branched PFOS (br-PFOS) in 1 day even at room temperature (25 °C). The effects of the iron and cobalt metal centers, reaction pH, and several reductants (NaBH4, nanosized zerovalent zinc (nZn0), and TiIII citrate) were systematically investigated. Based on the analysis of the products and previously published reports, a new possible defluorination pathway of branched PFOS is also proposed.

Inhibitors of bacterial RNA polymerase transcription complex.

A series of hybrid compounds that incorporated anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Synthesis, in vitro transcription inhibition assays, and biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with MICs as low as 3.1 µM. A structure activity relationship study identified the key structural components necessary for inhibition of both bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy and resistance passaging using Gram-positive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.

Unusual Alternating Crystallization-Induced Emission Enhancement Behavior in Nonconjugated ω-Phenylalkyl Tropylium Salts.

The alternating physical properties, especially melting points, of α,ω-disubstituted n-alkanes and their parent n-alkanes had been known since Baeyer's report in 1877. There is, however, no general and comprehensive explanation for such a phenomenon. Herein, we report the synthesis and examination of a series of novel ω-phenyl n-alkyl tropylium tetrafluoroborates, which also display alternation in their physicochemical characters. Despite being organic salts, the compounds with odd numbers of carbons in the alkyl bridge exist as room temperature ionic liquids. In stark contrast to this, the analogues with even numbers of carbons in the linker are crystalline solids. These solid nonconjugated molecules exhibit curious photoluminescent properties, which can be attributed to their ability to form through-space charge-transfer complexes to cause crystallization-induced emission enhancement. Most notably, the compound with the highest photoluminescent quantum yield in this series showed an unusual arrangement of carbocationic dimer in the solid state. A combination of XRD analysis and ab initio calculations revealed interesting insights into these systems.

Hierarchical Spin-Crossover Cooperativity in Hybrid 1D Chains of FeII -1,2,4-Triazole Trimers Linked by [Au(CN)2 ]- Bridges.

Foremost, practical applications of spin-crossover (SCO) materials require control of the nature of the spin-state coupling. In existing SCO materials, there is a single, well-defined dimensionality relevant to the switching behavior. A new material, consisting of 1,2,4-triazole-based trimers coordinated into 1D chains by [Au(CN)2 ]- and spaced by anions and exchangeable guests, underwent SCO defined by elastic coupling across multiple dimensional hierarchies. Detailed structural, vibrational, and theoretical studies conclusively confirmed that intra-trimer coupling was an order of magnitude greater than the intramolecular coupling, which was an order of magnitude greater than intermolecular coupling. As such, a clear hierarchy on the nature of elastic coupling in SCO materials was ascertained for the first time, which is a necessary step for the technological development of molecular switching materials.

Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa.

The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.

The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors.

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

Ultra-Low Molecular Weight Photoswitchable Hydrogelators.

Two photoswitchable arylazopyrozoles form hydrogels at a concentration of 1.2 % (w/v). With a molecular weight of 258.28 g mol-1 , these are the lowest known molecular weight hydrogelators that respond reversibly to light. Photoswitching of the E- to the Z-form by exposure to 365 nm light results in a macroscopic gel→sol transition; nearly an order of magnitude reduction in the measured elastic and loss moduli. In the case of the meta-arylazopyrozole, cryogenic transmission electron microscopy suggests that the 29±7 nm wide sheets in the E-gel state narrow to 13±2 nm upon photoswitching to the predominantly Z-solution state. Photoswitching for meta-arylazopyrozole is reversible through cycles of 365 nm and 520 nm excitation with little fatigue. The release of a rhodamine B dye encapsulated in gels formed by the arylazopyrozoles is accelerated more than 20-fold upon photoswitching with 365 nm light, demonstrating these materials are suitable for light-controlled cargo release.

Synthetic Bilayers on Mica from Self-Assembly of Hydrogen-Bonded Triazines.

This study describes organic thin films prepared under a range of conditions from a model series of bis-N-alkyl chloro-triazines functionalized with short alkyl chains from ethyl to hexyl. The pure films were characterized using atomic force microscopy (AFM), X-ray diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). When cast on mica, these compounds assemble as crystalline sheets made up of a synthetic bilayer along the crystallographic ab-plane with an internal hydrogen-bonded domain between external alkyl chains. These micron-scale surfaces stack along the c-axis, and increasing the alkyl chain length results in changes to the crystal morphology from needles to nanoscale plates. Thicker films produce nanoscale, pyramidal stacks of bilayers. Compared to atomically flat mica, a rougher, unetched silicon substrate produced irregular domains in the secondary bilayer. Films of mixtures comprising the ethyl derivative with butyl, pentyl, or hexyl derivative were imaged using time-of-flight secondary-ion mass spectrometry (ToF-SIMS) that indicated a trend toward a constant stoichiometry with increasing alkyl chain length. AFM of mixed films on mica showed single bilayers of height <2 nm, with an acceptable correlation to the XRD measurements, supporting a constant stoichiometry. These materials permit easy modification of mica to a micron-scale, atomically flat hydrophobic surface, and the use of mixtures with different alkyl chain lengths suggests a method to improve the quality of functional organic thin films.

A Rare Example of a Complete, Incomplete, and Non-Occurring Spin Transition in a [Fe2L3]X4 Series Driven by a Combination of Solvent-and Halide-Anion-Mediated Steric Factors.

A trend between the degree of steric congestion of the Fe(II) coordination environment and the extent of spin transition (percentage completeness) has been observed in a series of halide salts of a dinuclear triple helicate architecture with the general form [Fe2L3]X4 (where X = Cl- for 1, Br- for 2, and (I-)3/I3- for 3, and L is (1E,1'E)-N,N'-(oxybis(4,1-phenylene))bis(1-(1H-imidazol-4-yl)methanimine). Crystal packing densities of adjacent helicates were found to decrease with increasing anion size. Greater steric congestion by neighboring helicates favored the [HS-HS] state of the dinuclear triple helicate architecture. As a result, the highly crowded Cl- salt (1) did not undergo spin-crossover (SCO), the more congested Br- salt (2) underwent an incomplete solvent-dependent transition, and the least crowded (I-)3/I3- analogue (3) exhibited a full SCO from the [HS-HS] ↔ [LS-LS] state. Furthermore, an interesting two-step transition was observed in the Br- salt, exhibiting a 28 K thermal hysteresis in the higher temperature step, the largest thermal hysteresis reported to date for a Fe(II) dinuclear triple helicate system. Variable-temperature single-crystal X-ray diffraction (SCXRD) analysis of 2 demonstrated that this two-step profile was found to be the result of crystallographic parameters evolving in a two-step manner with temperature, rather than a crystallographic phase change.

Guest Removal and External Pressure Variation Induce Spin Crossover in Halogen-Functionalized 2-D Hofmann Frameworks.

The effect of halogen functionalization on the spin crossover (SCO) properties of a family of 2-D Hofmann framework materials, [FeIIPd(CN)4(thioX)2]·2H2O (X = Cl and Br; thioCl = (E)-1-(5-chlorothiophen-2-yl)-N-(4H-1,2,4-triazol-4-yl)methanimine) and thioBr = (E)-1-(5-bromothiophen-2-yl)-N-(4H-1,2,4-triazol-4-yl)methanimine)), is reported. Inclusion of both the chloro- and bromo-functionalized ligands into the Hofmann-type frameworks (1Cl·2H2O and 2Br·2H2O) results in a blocking of spin-state transitions due to internal chemical pressure effects derived by the collective steric bulk of the halogen atoms and guest molecules. Cooperative one-step SCO transitions are revealed by either guest removal or the application of external physical pressure. Notably, removal of solvent water reveals a robust framework scaffold with only marginal variation between the solvated and desolvated structures (as investigated by powder and single crystal X-ray diffraction). Yet, one-step complete SCO transitions are revealed in 1Cl and 2Br with a transition temperature shift between the analogues due to various steric, structural, and electronic considerations. SCO can also be induced in the solvated species, 1Cl·2H2O and 2Br·2H2O, with the application of physical pressure, revealing a complete one-step SCO transition above 0.62 GPa (as investigated by magnetic susceptibility and single crystal X-ray diffraction measurements).

Multifunctional chiral aminophosphines for enantiodivergent catalysis in a palladium-catalyzed allylic alkylation reaction.

Trifunctional MAP-based chiral phosphines were tested as new ligands in a Pd-catalyzed asymmetric allylic alkylation, demonstrating fast and enantiodivergent catalysis. The palladium complexes of representative ligands by X-ray analysis revealed a novel mode of P,N-coordination of the ligand to the palladium center, which may contribute to switching the sense of the asymmetric induction via combined steric and tunable H-bonding interactions between the metal complex and the substrates.

Halide Anion Triggered Reactions of Michael Acceptors with Tropylium Ion.

Tropylium bromide undergoes noncatalyzed, regioselective additions to a large variety of Michael acceptors. In this way, acrylic esters are converted into ß-bromo-α-cycloheptatrienylpropionic esters. The reactions are interpreted as nucleophilic attack of bromide ions at the electron-deficient olefins and the approach of the tropylium ion to the incipient carbanion. Quantum chemical calculations were performed to elucidate the analogy to the amine- or phosphine-catalyzed Rauhut-Currier reactions. Subsequent synthetic transformations of the bromo-cycloheptatrienylated adducts are reported.

Gel- and Solid-State-Structure of Dialanine and Diphenylalanine Amphiphiles: Importance of C⋠⋠⋠H Interactions in Gelation.

To investigate the role of the capping group in the solution and solid-state self-assembly of short peptide amphiphiles, dialanine and diphenylalanine have been linked via the N-terminus to a benzene (phenyl) and 3-naphthyl capping groups using three different methylene linkers; (CH2 )n , n=0-4 for the benezene and 0, 1 and 2 for the naphthalene capping group. Atomic force microscopy (AFM), oscillatory rheology, circular dichroism (CD), and IR analysis have been employed to understand the properties of these peptide-based hydrogels. Several X-ray structures of these short peptide gelators give useful conformational information regarding packing. A comparison of these solid state structures with their gel state properties yielded greater insights into the process of self-assembly in short peptide gelators, particularly in terms of the important role of C⋅⋅⋅H interactions appear to play in determining if a short aromatic peptide does form a gel or not.

Exploration of the Differences between Amine and Thiolate Addition to Acetylenedicarboxylates.

Nucleophilic addition of thiolates to diethyl acetylenedicarboxylate in chloroform at room temperature affords solely the meso dithioaddition product, whereas the addition of amines in ethanol gives only the corresponding (Z)-enamine, as confirmed by X-ray crystal analysis. The monoaddition product of thiolate addition, prepared and isolated at lower temperatures, also exhibited (Z)-stereochemistry. The accompanying computational study on simplified model systems explains the reasons for the observed stereochemistry and for acetylenedicarboxylate readily undergoing two addition reactions with thiolate nucleophiles and the (Z)-enamine being much less reactive toward addition of thiolate or amine nucleophiles.