Carbon-Phosphorus Coupling from C

With the aim of exploiting new organometallic species for cross-coupling reactions, we report here on the AuIII -mediated Caryl -P bond formation occurring upon reaction of C^N cyclometalated AuIII complexes with phosphines. The [Au(C^N)Cl2 ] complex 1 featuring the bidentate 2-benzoylpyridine (CCO N) scaffold was found to react with PTA (1,3,5-triaza-7-phosphaadamantane) under mild conditions, including in water, to afford the corresponding phosphonium 5 through C-P reductive elimination. A mechanism is proposed for the title reaction based on in situ 31 P{1 H} NMR and HR-ESI-MS analyses combined with DFT calculations. The C-P coupling has been generalized to other C^N cyclometalated AuIII complexes and other tertiary phosphines. Overall, this work provides new insights into the reactivity of cyclometalated AuIII compounds and establishes initial structure-activity relationships to develop AuIII -mediated C-P cross-coupling reactions.

Sesquiterpene Synthase-Catalysed Formation of a New Medium-Sized Cyclic Terpenoid Ether from Farnesyl Diphosphate Analogues.

Terpene synthases catalyse the first step in the conversion of prenyl diphosphates to terpenoids. They act as templates for their substrates to generate a reactive conformation, from which a Mg2+ -dependent reaction creates a carbocation-PPi ion pair that undergoes a series of rearrangements and (de)protonations to give the final terpene product. This tight conformational control was exploited for the (R)-germacrene A synthase- and germacradien-4-ol synthase-catalysed formation of a medium-sized cyclic terpenoid ether from substrates containing nucleophilic functional groups. Farnesyl diphosphate analogues with a 10,11-epoxide or an allylic alcohol were efficiently converted to a 11-membered cyclic terpenoid ether that was characterised by HRMS and NMR spectroscopic analyses. Further experiments showed that other sesquiterpene synthases, including aristolochene synthase, δ-cadinene synthase and amorphadiene synthase, yielded this novel terpenoid from the same substrate analogues. This work illustrates the potential of terpene synthases for the efficient generation of structurally and functionally novel medium-sized terpene ethers.

Oxidation of Polynuclear Aromatic Hydrocarbons using Ruthenium-Ion-Catalyzed Oxidation: The Role of Aromatic Ring Number in Reaction Kinetics and Product Distribution.

Oxidation of aromatic hydrocarbons with differing numbers of fused aromatic rings (2-5), have been studied in two solvent environments (monophasic and biphasic) using ruthenium-ion-catalyzed oxidation (RICO). RICO reduces the aromaticity of the polyaromatic core of the molecule in a controlled manner by selective oxidative ring opening. Moreover, the nature of the solvent system determines the product type and distribution, for molecules with more than two aromatic rings. Competitive oxidation between substrates with different numbers of aromatic rings has been studied in detail. It was found that the rate of polyaromatic hydrocarbon oxidation increases with the number of fused aromatic rings. A similar trend was also identified for alkylated aromatic hydrocarbons. The proof-of-concept investigation provides new insight into selective oxidation chemistry for upgrading of polyaromatic molecules.

Mechanistic Insights into Selective Oxidation of Polyaromatic Compounds using RICO Chemistry.

Ruthenium-ion-catalyzed oxidation (RICO) of polyaromatic hydrocarbons (PAHs) has been studied in detail using experimental and computational approaches to explore the reaction mechanism. DFT calculations show that regioselectivity in these reactions can be understood in terms of the preservation of aromaticity in the initial formation of a [3+2] metallocycle intermediate at the most-isolated double bond. We identify two competing pathways: C-C bond cleavage leading to a dialdehyde and C-H activation followed by H migration to the RuOx complex to give diketones. Experimentally, the oxidation of pyrene and phenanthrene has been carried out in monophasic and biphasic solvent systems. Our results show that diketones are the major product for both phenanthrene and pyrene substrates. These diketone products are shown to be stable under our reaction conditions so that higher oxidation products (acids and their derivatives) are assigned to the competing pathway through the dialdehyde. Experiments using 18 O-labelled water do show incorporation of oxygen from the solvents into products, but this may take place during the formation of the reactive RuO4 species rather than directly during PAH oxidation. When the oxidation of pyrene is carried out using D2 O, a kinetic isotope effect (KIE) is observed implying that water is involved in the rate-determining step leading to the diketone products.

Selective oxidation of alkyl-substituted polyaromatics using ruthenium-ion-catalyzed oxidation.

Ruthenium-ion-catalyzed oxidation of a range of alkylated polyaromatics has been studied. 2-Ethylnaphthalene was used as a model substrate, and oxidation can be performed in either a conventional biphasic or in a monophasic solvent system. In either case the reaction rates and product selectivity are identical. The reaction products indicate that the aromatic ring system is oxidized in preference to the alkyl chain. This analysis is possible due to the development of a quantitative NMR protocol to determine the relative amounts of aliphatic and aromatic protons. From a systematic set of substrates we show that as the length of the alkyl chain substituent on a polyaromatic increases, the proportion of products in which the chain remains attached to the aromatic system increases. Larger polyaromatic systems, based on pyrene and phenanthrene, show greater reactivity than those with fewer aromatic rings, and the alkyl chains are more stable to oxidation.

Partial oxidation of ethane to oxygenates using Fe- and Cu-containing ZSM-5.

Iron and copper containing ZSM-5 catalysts are effective for the partial oxidation of ethane with hydrogen peroxide giving combined oxygenate selectivities and productivities of up to 95.2% and 65 mol kgcat(-1) h(-1), respectively. High conversion of ethane (ca. 56%) to acetic acid (ca. 70% selectivity) can be observed. Detailed studies of this catalytic system reveal a complex reaction network in which the oxidation of ethane gives a range of C2 oxygenates, with sequential C-C bond cleavage generating C1 products. We demonstrate that ethene is also formed and can be subsequently oxidized. Ethanol can be directly produced from ethane, and does not originate from the decomposition of its corresponding alkylperoxy species, ethyl hydroperoxide. In contrast to our previously proposed mechanism for methane oxidation over similar zeolite catalysts, the mechanism of ethane oxidation involves carbon-based radicals, which lead to the high conversions we observe.

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor.

The Bohlmann-Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow reactor or using a conductive heating flow platform for the continuous processing of material. In the Bohlmann-Rahtz reaction, the use of a Brønsted acid catalyst allows Michael addition and cyclodehydration to be carried out in a single step without isolation of intermediates to give the corresponding trisubstituted pyridine as a single regioisomer in good yield. Furthermore, 3-substituted propargyl aldehydes undergo Hantzsch dihydropyridine synthesis in preference to Bohlmann-Rahtz reaction in a very high yielding process that is readily transferred to continuous flow processing.

Catalytic and mechanistic insights of the low-temperature selective oxidation of methane over Cu-promoted Fe-ZSM-5.

The partial oxidation of methane to methanol presents one of the most challenging targets in catalysis. Although this is the focus of much research, until recently, approaches had proceeded at low catalytic rates (<10 h(-1)), not resulted in a closed catalytic cycle, or were unable to produce methanol with a reasonable selectivity. Recent research has demonstrated, however, that a system composed of an iron- and copper-containing zeolite is able to catalytically convert methane to methanol with turnover frequencies (TOFs) of over 14,000 h(-1) by using H(2)O(2) as terminal oxidant. However, the precise roles of the catalyst and the full mechanistic cycle remain unclear. We hereby report a systematic study of the kinetic parameters and mechanistic features of the process, and present a reaction network consisting of the activation of methane, the formation of an activated hydroperoxy species, and the by-production of hydroxyl radicals. The catalytic system in question results in a low-energy methane activation route, and allows selective C(1)-oxidation to proceed under intrinsically mild reaction conditions.

Double blind randomized controlled trial of deep brain stimulation for obsessive-compulsive disorder: Clinical trial design.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

Continuous flow processing from microreactors to mesoscale: the Bohlmann-Rahtz cyclodehydration reaction.

The cyclodehydration of a number of Bohlmann-Rahtz aminodienones exemplifies the use of continuous flow processing to transfer operations from commercial microreactors and microwave batch reactors to mesoscale production using different technology platforms, including a microwave flow reactor.

Uptake and localisation of rhenium fac-tricarbonyl polypyridyls in fluorescent cell imaging experiments.

The synthesis of a series of rhenium fac tricarbonyl bisimine complexes and their application as lumophores in fluorescence imaging of yeast and human adenocarcinoma cells is reported. A wide range of complexes are synthesised with varying charges and lipophilicities, all of which have photophysical properties which make them suitable as cell imaging agents. After attempts to apply these as imaging agents in various strains of yeast which showed limited uptake, an investigation was undertaken of their applications as imaging agents in mammalian cells. In general the uptake was high and short-term toxicity and photobleaching appear to be low. The patterns of uptake and localisation are correlated with structural and electronic features of the complexes in an attempt to establish ground-rules for the design and application of rhenium complexes in imaging of eukaryotes.

Locus-specific microemulsion catalysts for sulfur mustard (HD) chemical warfare agent decontamination.

The rates of catalytic oxidative decontamination of the chemical warfare agent (CWA) sulfur mustard (HD, bis(2-chlororethyl) sulfide) and a range (chloroethyl) sulfide simulants of variable lipophilicity have been examined using a hydrogen peroxide-based microemulsion system. SANS (small-angle neutron scattering), SAXS (small-angle X-ray scattering), PGSE-NMR (pulsed-gradient spin-echo NMR), fluorescence quenching, and electrospray mass spectroscopy (ESI-MS) were implemented to examine the distribution of HD, its simulants, and their oxidation/hydrolysis products in a model oil-in-water microemulsion. These measurements not only present a means of interpreting decontamination rates but also a rationale for the design of oxidation catalysts for these toxic materials. Here we show that by localizing manganese-Schiff base catalysts at the oil droplet-water interface or within the droplet core, a range of (chloroethyl) sulfides, including HD, spanning some 7 orders of octanol-water partition coefficient (K(ow)), may be oxidized with equal efficacy using dilute (5 wt. % of aqueous phase) hydrogen peroxide as a noncorrosive, environmentally benign oxidant (e.g., t(1/2) (HD) approximately 18 s, (2-chloroethyl phenyl sulfide, C(6)H(5)SCH(2)CH(2)Cl) approximately 15 s, (thiodiglycol, S(CH(2)CH(2)OH)(2)) approximately 19 s {20 degrees C}). Our observations demonstrate that by programming catalyst lipophilicity to colocalize catalyst and substrate, the inherent compartmentalization of the microemulsion can be exploited to achieve enhanced rates of reaction or to exert control over product selectivity. A combination of SANS, ESI-MS and fluorescence quenching measurements indicate that the enhanced catalytic activity is due to the locus of the catalyst and not a result of partial hydrolysis of the substrate.

Exo-Functionalized Metallacages as Host-Guest Systems for the Anticancer Drug Cisplatin.

Within the framework of designing new self-assembled metallosupramolecular architectures for drug delivery, seven [Pd2L4]4+ metallacages (L = 2,6-bis(pyridine-3-ylethynyl)pyridine) featuring different groups in exo-position, selected to enhance the cage solubility in aqueous environment, were synthesized. Thus, carboxylic acids, sugars, and PEG groups were tethered to the bispyridyl ligands directly or via disulfide bond formation, as well as via click chemistry. The ligands and respective cages were characterized by different methods, including NMR spectroscopy and high-resolution electrospray mass spectrometry (HR-ESI-MS). While the two ligands featuring carboxylic acid-functionalized groups showed improved solubility in water, the other ligands were soluble only in organic solvents. Unfortunately, all the respective self-assembled cages were also insoluble in water. Afterwards, the encapsulation properties of the anticancer drug cisplatin in selected [Pd2L4]X4 cages (X = NO 3 - , BF 4 - ) were studied by 1H, 1H DOSY, and 195Pt NMR spectroscopy. The effect of the counter ions as well as of the polarity of the solvent in the drug encapsulation process were also investigated, and provided useful information on the host-guest properties of these experimental drug delivery systems. Our results provide further experimental support for previous studies that suggest the desolvation of guests from surrounding solvent molecules and the resulting solvent rearrangement may actually be the primary driving force for determining guest binding affinities in metallacages, in the absence of specific functional group interactions.

Aqueous Au-Pd colloids catalyze selective CH4 oxidation to CH3OH with O2 under mild conditions.

The selective oxidation of methane, the primary component of natural gas, remains an important challenge in catalysis. We used colloidal gold-palladium nanoparticles, rather than the same nanoparticles supported on titanium oxide, to oxidize methane to methanol with high selectivity (92%) in aqueous solution at mild temperatures. Then, using isotopically labeled oxygen (O2) as an oxidant in the presence of hydrogen peroxide (H2O2), we demonstrated that the resulting methanol incorporated a substantial fraction (70%) of gas-phase O2 More oxygenated products were formed than the amount of H2O2 consumed, suggesting that the controlled breakdown of H2O2 activates methane, which subsequently incorporates molecular oxygen through a radical process. If a source of methyl radicals can be established, then the selective oxidation of methane to methanol using molecular oxygen is possible.

Tuning graphitic oxide for initiator- and metal-free aerobic epoxidation of linear alkenes.

Graphitic oxide has potential as a carbocatalyst for a wide range of reactions. Interest in this material has risen enormously due to it being a precursor to graphene via the chemical oxidation of graphite. Despite some studies suggesting that the chosen method of graphite oxidation can influence the physical properties of the graphitic oxide, the preparation method and extent of oxidation remain unresolved for catalytic applications. Here we show that tuning the graphitic oxide surface can be achieved by varying the amount and type of oxidant. The resulting materials differ in level of oxidation, surface oxygen content and functionality. Most importantly, we show that these graphitic oxide materials are active as unique carbocatalysts for low-temperature aerobic epoxidation of linear alkenes in the absence of initiator or metal. An optimum level of oxidation is necessary and materials produced via conventional permanganate-based methods are far from optimal.

A general method for the alpha-acyloxylation of carbonyl compounds.

[chemical reaction: see text]. A simple, one-pot method for the alpha-acyloxylation of carbonyl compounds that proceeds at room temperature in the presence of both moisture and air has been developed. Treatment of a variety of aldehydes and both cyclic and acyclic ketones with N-methyl-O-benzoylhydroxylamine hydrochloride provides the alpha-functionalized product in 69-92% isolated yield. The transformation is tolerant of a wide range of functional groups and, significantly, is regiospecific in the discrimination of secondary over primary centers in the case of nonsymmetrical substrates.

A simple method for the alpha-oxygenation of aldehydes.

A mild, efficient and general method for the chemospecific alpha-oxygenation of aldehydes is described. Treatment of a series of aldehydes with N-tert-butyl-O-benzoyl hydroxylamine hydrochloride gives the corresponding alpha-oxygenated carbonyl via a proposed pericyclic rearrangement process.