Rhodocenium Functionalization Enabled by Half-Sandwich Capping, Zincke Reaction, Diazoniation and Sandmeyer Chemistry.

In continuation of our exploration of metallocenium chemistry we report here on innovative ways toward monofunctionalized rhodocenium salts applying half-sandwich capping reactions of cyclopentadienyl rhodium(III) halide synthons with cyclopentadienyl ylides containing pyridine, phosphine or dinitrogen leaving groups, followed by Zincke and Sandmeyer reactions. Thereby amino, diazonio, bromo, azido and iodo rhodocenium salts containing valuable functional groups are accessible for the first time. Target compounds were characterized by spectroscopic (1H/13C/103Rh-NMR, IR, HR-MS), structural (single crystal XRD) and electrochemical (CV) methods and their properties were compared to those of isoelectronic cobaltocenium compounds. These new functionalized rhodocenium complexes significantly expand the so far extremely limited chemical space of rhodocenium salts with promising options for the future development in the area of rhodocenium chemistry.

Cationic Cycloheptatrienyl Cyclopentadienyl Manganese Sandwich Complexes: Tromancenium Explored with High-Power LED Photosynthesis.

In this contribution, we revisit the neglected and forgotten cationic, air-stable, 18-valence electron, heteroleptic sandwich complex (cycloheptatrienyl)(cyclopentadienyl)manganese, which was reported independently by Fischer and by Pauson about 50 years ago. Using advanced high-power LED photochemical synthesis, an expedient rapid access to the parent complex and to functionalized derivatives with alkyl, carboxymethyl, bromo, and amino substituents was developed. A thorough study of these "tromancenium" salts by a range of spectroscopic techniques (1H/13C/55Mn-NMR, IR, UV-vis, HRMS, XRD, XPS, EPR), cyclic voltammetry (CV), and quantum chemical calculations (DFT) shows that these manganese sandwich complexes are unique metallocenes with quite different chemical and physical properties in comparison to those of isoelectronic cobaltocenium salts or (cycloheptatrienyl)(cyclopentadienyl) sandwich complexes of the early transition metals. Electrochemically, all tromancenium ions undergo a chemically partially reversible oxidation and a chemically irreversible reduction at half-wave or peak potentials that respond to the substituents at the Cp deck. As exemplarily shown for the parent tromancenium ion, the product generated during the irreversible reduction process reverts at least partially to the starting material upon reoxidation. Quantum-chemical calculations of the parent tromancenium salt indicate that metal-ligand bonding is distinctly weaker for the cycloheptatrienyl ligand in comparison to that of the cyclopentadienyl ligand. Both the HOMO and the LUMO are metal and cycloheptatrienyl-ligand centered, indicating that chemical reactions will occur either metal-based or at the seven-membered ring, but not on the cyclopentadienyl ligand.

Oxidative access via aqua regia to an electrophilic, mesoionic dicobaltoceniumyltriazolylidene gold(III) catalyst.

A gold(III) complex with the hitherto most electron poor mesoionic carbene ligand is presented. Aqua regia was the oxidizing agent of choice for the synthesis of this unusual organometallic compound. The AuIII complex is redox-rich, and also acts as a catalyst for oxazole formation, delivering selectively a completely different isomer compared to its AuI congener.

Efficient Z-Selective Semihydrogenation of Internal Alkynes Catalyzed by Cationic Iron(II) Hydride Complexes.

The bench-stable cationic bis(σ-B-H) aminoborane complex [Fe(PNPNMe-iPr)(H)(η2-H2B = NMe2)]+ (2) efficiently catalyzes the semihydrogenation of internal alkynes, 1,3-diynes and 1,3-enynes. Moreover, selective incorporation of deuterium was achieved in the case of 1,3-diynes and 1,3-enynes. The catalytic reaction takes place under mild conditions (25 °C, 4-5 bar H2 or D2) in 1 h, and alkenes were obtained with high Z-selectivity for a broad scope of substrates. Mechanistic insight into the catalytic reaction, explaining also the stereo- and chemoselectivity, is provided by means of DFT calculations. Intermediates featuring a bisdihydrogen moiety [Fe(PNPNMe-iPr)(η2-H2)2]+ are found to play a key role. Experimental support for such species was unequivocally provided by the fact that [Fe(PNPNMe-iPr)(H)(η2-H2)2]+ (3) exhibited the same catalytic activity as 2. The novel cationic bisdihydrogen complex 3 was obtained by protonolysis of [Fe(PNPNMe-iPr)(H)(η2-AlH4)]2 (1) with an excess of nonafluoro-tert-butyl alcohol.

Redox-Rich Metallocene Tetrazene Complexes: Synthesis, Structure, Electrochemistry, and Catalysis.

Thermal or photochemical metal-centered cycloaddition reactions of azidocobaltocenium hexafluoridophosphate or azidoferrocene with (cyclooctadiene)(cyclopentadienyl)cobalt(I) afforded the first metallocenyl-substituted tetrazene cyclopentadienyl cobalt complexes together with azocobaltocenium or azoferrocene as side products. The trimetallic CpCo compounds are highly conjugated, colored, and redox-active metallo-aromatic compounds, as shown by their spectroscopic, structural, and electrochemical properties. The CpCo-tetrazenido complex with two terminally appended cobaltocene units catalyzes electrochemical proton reduction from acetic acid at a mild overpotential (0.35 V). Replacing cobaltocene with ferrocene moieties rendered the complex inactive toward catalysis.

Cobaltocenylidene: A Mesoionic Metalloceno Carbene, Stabilized in a Gold(III) Complex.

Oxidative addition of cobaltoceniumdiazonium bis(hexafluoridophosphate) with (pseudo)halide aurates gave gold(III) complexes containing zwitterionic cobaltoceniumide as a ligand. Its selenium derivative, cobaltoceniumselenolate, was obtained by an electrophilic aromatic substitution reaction of iodocobaltocenium iodide with Na2 Se. Spectroscopic and structural data in combination with DFT calculations showed that this cobaltocenylidene species is a mesoionic carbene quite different from common N-heterocyclic carbenes. Its ligand properties (TEP, singlet-triplet gap, nucleophilicity, π-acidity, Brønsted basicity) are in part comparable to those of cyclic (amino)(alkyl/aryl)carbenes. Electrochemistry data showed that the mesoionic cobaltoceniumides are more electron-rich than their parent ferrocenes. The reversible reduction of the tricyanido gold complex appears 50 mV negative of the cobaltocenium/cobaltocene couple, whereas that of the selenide derivative is shifted cathodically by 550 mV.

Highly Electrophilic, Catalytically Active and Redox-Responsive Cobaltoceniumyl and Ferrocenyl Triazolylidene Coinage Metal Complexes.

A convenient access to a triad of triazoles with ferrocenyl and cobaltoceniumyl substituents is reported. N-Alkylation, deprotonation and metalation with CuI /AgI /AuI synthons affords the heteroleptic triazolylidene complexes. Due to the combination of neutral, electron-donating ferrocenyl substituents and cationic, strongly electron-withdrawing cobaltocenium substituents, the mesoionic carbene (MIC) ligands of these complexes are electronically interesting "push-pull", "pull-push" and "pull-pull" metalloligands with further switchable redox states based on their fully reversible FeII /FeIII , (ferrocene/ferrocenium) and CoIII /CoII , (cobaltocenium/cobaltocene) redox couples. These are the first examples of metal complexes of (di)cationic NHC ligands based on cobaltoceniumyl substituents. DFT calculated Tolman electronic parameter (TEP) of the new MIC ligands, show these metalloligands to be extremely electron-poor NHCs with properties unmatched in other carbene chemistry. Utilization of these multimetallic electronically tunable compounds in catalytic oxazoline synthesis and in antitumor studies are presented. Remarkably, 1 mol % of the AuI complex with the dicationic MIC ligand displays full catalytic conversion, without the need for any other additives, in less than 2 hours at ambient temperatures. These results thus firmly establish these new classes of cobaltoceniumyl based (di)cationic MIC ligands as prominent players in several branches of chemistry.

In Vitro and Ex Vivo Evaluation of Novel Curcumin-Loaded Excipient for Buccal Delivery.

This study aimed to develop a mucoadhesive polymeric excipient comprising curcumin for buccal delivery. Curcumin encompasses broad range of benefits such as antioxidant, anti-inflammatory, and chemotherapeutic activity. Hyaluronic acid (HA) as polymeric excipient was modified by immobilization of thiol bearing ligands. L-Cysteine (SH) ethyl ester was covalently attached via amide bond formation between cysteine and the carboxylic moiety of hyaluronic acid. Succeeded synthesis was proved by H-NMR and IR spectra. The obtained thiolated polymer hyaluronic acid ethyl ester (HA-SH) was evaluated in terms of stability, safety, mucoadhesiveness, drug release, and permeation-enhancing properties. HA-SH showed 2.75-fold higher swelling capacity over time in comparison to unmodified polymer. Furthermore, mucoadhesion increased 3.4-fold in case of HA-SH and drug release was increased 1.6-fold versus HA control, respectively. Curcumin-loaded HA-SH exhibits a 4.4-fold higher permeation compared with respective HA. Taking these outcomes in consideration, novel curcumin-loaded excipient, namely thiolated hyaluronic acid ethyl ester appears as promising tool for pharyngeal diseases.

Next generation of buccadhesive excipient: Preactivated carboxymethyl cellulose.

AIM: Assessment of preactivated carboxymethyl cellulose as potential excipient for buccal drug delivery. METHODS: Firstly, carboxymethyl cellulose (CMC) and cysteine (SH) were covalently coupled via amide bond formation to obtain thiolated carboxymethyl cellulose (CMC-SH). Further, preactivated carboxymethyl cellulose (CMC-S-S-MNA) was obtained by preactivation with 2-mercaptonicotinic acid (MNA). Sulforhodamine 101 (SRH101) was used as a model drug for permeation study through buccal mucosa. CMC-S-S-MNA was evaluated with respect to mucoadhesive and permeation enhancing effect and cytotoxicity. RESULTS: Thiolated carboxymethyl cellulose exhibited a total amount of 112.46 ± 0.46 thiol groups. CMC-S-S-MNA exhibited around 50% of preactivated thiol groups. The preactivated polymer showed no toxic effect. Furthermore, compared to unmodified CMC, CMC-S-S-MNA revealed 3.0-fold improved mucoadhesive properties according to the rotating cylinder method and 8.8-fold enhancement in mucoadhesiveness by tensile assay, respectively. CONCLUSION: Preactivated carboxymethyl cellulose fulfills the requirements as potential excipient of being mucoadhesive and permeation enhancing for the buccal drug delivery.

Enhanced kinetic stability of pure and Y-doped tetragonal ZrO2.

The kinetic stability of pure and yttrium-doped tetragonal zirconia (ZrO2) polymorphs prepared via a pathway involving decomposition of pure zirconium and zirconium + yttrium isopropoxide is reported. Following this preparation routine, high surface area, pure, and structurally stable polymorphic modifications of pure and Y-doped tetragonal zirconia are obtained in a fast and reproducible way. Combined analytical high-resolution in situ transmission electron microscopy, high-temperature X-ray diffraction, and chemical and thermogravimetric analyses reveals that the thermal stability of the pure tetragonal ZrO2 structure is very much dominated by kinetic effects. Tetragonal ZrO2 crystallizes at 400 °C from an amorphous ZrO2 precursor state and persists in the further substantial transformation into the thermodynamically more stable monoclinic modification at higher temperatures at fast heating rates. Lower heating rates favor the formation of an increasing amount of monoclinic phase in the product mixture, especially in the temperature region near 600 °C and during/after recooling. If the heat treatment is restricted to 400 °C even under moist conditions, the tetragonal phase is permanently stable, regardless of the heating or cooling rate and, as such, can be used as pure catalyst support. In contrast, the corresponding Y-doped tetragonal ZrO2 phase retains its structure independent of the heating or cooling rate or reaction environment. Pure tetragonal ZrO2 can now be obtained in a structurally stable form, allowing its structural, chemical, or catalytic characterization without in-parallel triggering of unwanted phase transformations, at least if the annealing or reaction temperature is restricted to T ≤ 400 °C.