Controlling the selectivity and efficiency of the hydrogen borrowing reaction by switching between rhodium and iridium catalysts.

The catalytic alkylation of ketones with alcohols via the hydrogen borrowing methodology (HB) has the potential to be a highly efficient approach for forming new carbon-carbon bonds. However, this transformation can result in more than one product being formed. The work reported here utilises bidentate triazole-carbene ligated iridium and rhodium complexes as catalysts for the selective formation of alkylated ketone or alcohol products. Switching from an iridium centre to a rhodium centre in the complex resulted in significant changes in product selectivity. Other factors - base, base loading, solvent and reaction temperature - were also investigated to tune the selectivity further. The optimised conditions were used to demonstrate the scope of the reaction across 17 ketones and 14 alcohols containing a variety of functional groups. A series of mechanistic investigations were performed to probe the reasons behind the product selectivity, including kinetic and deuterium studies.

Highly Efficient Rh(I) Homo- and Heterogeneous Catalysts for C-N Couplings via Hydrogen Borrowing.

Rhodium(I) complexes were explored as catalysts for the hydrogen borrowing reactions of amines and alcohols. Bidentate carbene-triazole ligands were readily synthesized via "click" reactions which allowed a diversity of ligand backbones to be accessed. The catalytic transformations are highly efficient, able to reach completion in under 6 h, and promote C-N bond formation across a range of primary alcohol and amine substrates. Moreover, site-selective catalysis can be achieved using substrates with more than one reactive site. A rhodium(I) complex covalently attached to a carbon black surface was also deployed in the hydrogen borrowing coupling reaction of aniline with benzyl alcohol. This represents the first report of a heterogeneous rhodium catalyst used for hydrogen borrowing.

Correction: Enhancements in catalytic reactivity and selectivity of homobimetallic complexes containing heteroditopic ligands.

Correction for 'Enhancements in catalytic reactivity and selectivity of homobimetallic complexes containing heteroditopic ligands' by Mark R. D. Gatus et al., Dalton Trans., 2017, 46, 7457-7466.

Gold(III) NHC Complexes for Catalyzing Dihydroalkoxylation and Hydroamination Reactions.

A gold(III) complex of an N-heterocyclic carbene based hemilabile ligand with two pendant pyrazole arms (1,3-bis((1H-pyrazol-3-yl)methyl)-2,3-dihydro-1H-imidazole, LH) was synthesized. Complex [LAu(III)Cl3] is an excellent catalyst for promoting dihydroalkoxylation at room temperature, even catalyzing this reaction at 0 °C. [LAu(III)Cl3] is one of the most efficient catalysts reported to date for the spirocyclization of alkynyl diols. Furthermore, [LAu(III)Cl3] catalyzed intra- and intermolecular hydroamination reactions, achieving good to excellent conversions. [LAu(III)Cl3] is a more efficient catalyst than a gold(I) analogue, [LAu(I)Cl]. The dependence of the quantity of weakly coordinating anion [BArF4]- ((3,5-trifluoromethyl)phenyl borate) present on catalysis efficiency was probed for the dihydroalkoxylation reaction. X-ray diffraction analysis of single crystals demonstrated the solid-state structure of gold complexes [LAu(III)Cl3] and [LAu(I)Cl], which displayed the expected square-planar and linear coordination geometries, respectively.

Enhancements in catalytic reactivity and selectivity of homobimetallic complexes containing heteroditopic ligands.

Rh(i) and Ir(i) homobimetallic complexes were synthesised using a heteroditopic ligand system on a xanthene scaffold containing a monodentate N-heterocyclic carbene ligand and a bidentate bis(pyrazol-1-yl)methane ligand. The complexes were tested as catalysts for the two-step dihydroalkoxylation and two-step hydroamination/hydrosilylation reactions. This is the first known report of an organometallic group 9 complex, Ir(i) bimetallic complex, 13, to selectively favour the opposite spirocyclisation product from that reported in the literature, 14cvs.14b. The Ir(i) homobimetallic complex catalyses the intramolecular hydroamination reaction of alkynamines efficiently and proved to be a highly active catalyst for promoting the subsequent hydrosilylation of the pyrrolines; completing the hydrosilylation reactions in less than 40 seconds. A chloro-bridged bimetallic species was observed in the solid state, revealing that the COD co-ligands present underwent an oxidation.

Ruthenium(ii) complexes of hemilabile pincer ligands: synthesis and catalysing the transfer hydrogenation of ketones.

A series of Ru(ii) complexes were synthesised based on a hemilabile pyrazole-N-heterocyclic carbene (NHC)-pyrazole (C3N2H3)CH2(C3N2H2)CH2(C3N2H3) NCN pincer ligand 1. All complexes were fully characterised using single crystal X-ray crystallography and multinuclear NMR spectroscopy. Hemilabile ligands provide flexible coordination modes for the coordinating metal ion which can play a significant effect on the efficiency and mechanism of catalysis by the resulting complex. Here we observed and isolated mono-, bi- and tri-dentate complexes of both Ag(i) and Ru(ii) with 1 in which the resultant coordination mode was controlled by careful reagent selection. The catalytic activity of the Ru(ii) complexes for the transfer hydrogenation reaction of acetophenone with isopropanol was investigated. The unexpected formation of the pentaborate anion, [B5O6(OH)4](-), during the synthesis of complex 6a was found to have an unexpected positive effect by enhancing the catalysis rate. This work provides insights into the roles that different coordination modes, counterions and ligand hemilability play on the catalytic activity in transfer hydrogenations.

A novel hot-melt extrusion formulation of albendazole for increasing dissolution properties.

The main aim of the research focused on the production of hot-melt extrusion (HME) formulations with increased dissolution properties of albendazole (ABZ). Therefore, HME was applied as a continuous manufacturing technique to produce amorphous solid dispersions of the poorly water soluble drug ABZ combined with the polymer matrix polyvinylpyrrolidone PVP K12. HME formulations of ABZ-PVP K12 comprised a drug content of 1%, 5% and 10% w/w. The main analytical characterisation techniques used were scanning electron microscopy (SEM), micro-computed tomography (µ-CT), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissolution profile studies. The application of SEM, XRPD and DSC evidenced drug physical transformation from crystalline to amorphous state and therefore, the achievement of an amorphous solid dispersion. The introduction of a novel technique, µ-CT, to characterise the internal structure of these materials revealed key information regarding materials distribution and void content. Dissolution profile studies evidenced a high increase in drug release profile compared to pure ABZ. These promising results can lead to a great enhancement of the oral bioavailability of ABZ dosage forms. Therefore, HME is a potential continuous manufacturing technique to overcome ABZ poor solubility properties and lead to a significant increase in the therapeutic effect.

Discovery of gigantic molecular nanostructures using a flow reaction array as a search engine.

The discovery of gigantic molecular nanostructures like coordination and polyoxometalate clusters is extremely time-consuming since a vast combinatorial space needs to be searched, and even a systematic and exhaustive exploration of the available synthetic parameters relies on a great deal of serendipity. Here we present a synthetic methodology that combines a flow reaction array and algorithmic control to give a chemical 'real-space' search engine leading to the discovery and isolation of a range of new molecular nanoclusters based on [Mo(2)O(2)S(2)](2+)-based building blocks with either fourfold (C4) or fivefold (C5) symmetry templates and linkers. This engine leads us to isolate six new nanoscale cluster compounds: 1, {Mo(10)(C5)}; 2, {Mo(14)(C4)4(C5)2}; 3, {Mo(60)(C4)10}; 4, {Mo(48)(C4)6}; 5, {Mo(34)(C4)4}; 6, {Mo(18)(C4)9}; in only 200 automated experiments from a parameter space spanning ~5 million possible combinations.

Titania-promoted carboxylic acid alkylations of alkenes and cascade addition-cyclizations.

Photochemical reactions employing TiO2 and carboxylic acids under dry anaerobic conditions led to several types of C-C bond-forming processes with electron-deficient alkenes. The efficiency of alkylation varied appreciably with substituents in the carboxylic acids. The reactions of aryloxyacetic acids with maleimides resulted in a cascade process in which a pyrrolochromene derivative accompanied the alkylated succinimide. The selectivity for one or other of these products could be tuned to some extent by employing the photoredox catalyst under different conditions. Aryloxyacetic acids adapted for intramolecular ring closures by inclusion of 2-alkenyl, 2-aryl, or 2-oximinyl functionality reacted rather poorly. Profiles of reactant consumption and product formation for these systems were obtained by an in situ NMR monitoring technique. An array of different catalyst forms were tested for efficiency and ease of use. The proposed mechanism, involving hole capture at the TiO2 surface by the carboxylates followed by CO2 loss, was supported by EPR spectroscopic evidence of the intermediates. Deuterium labeling indicated that the titania likely donates protons from surface hydroxyl groups as well as supplying electrons and holes, thus acting as both a catalyst and a reaction partner.

Interplay of ortho- with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes.

Sensitised photolyses of ethoxycarbonyl oximes of aromatic and heteroaromatic ketones yielded iminyl radicals, which were characterised by EPR spectroscopy. Iminyls with suitably placed arene or heteroarene acceptors underwent cyclisations yielding phenanthridine-type products from ortho-additions. For benzofuran and benzothiophene acceptors, spiro-cyclisation predominated at low temperatures, but thermodynamic control ensured ortho-products, benzofuro- or benzothieno-isoquinolines, formed at higher temperatures. Estimates by steady-state kinetic EPR established that iminyl radical cyclisations onto aromatics took place about an order of magnitude more slowly than prototypical C-centred radicals. The cyclisation energetics were investigated by DFT computations, which gave insights into factors influencing the two cyclisation modes.

Dissociation or cyclization: options for a triad of radicals released from oxime carbamates.

A set of oxime carbamates having N-alkyl and N,N-dialkyl substituents were prepared via carbonyldiimidazole intermediates. It was shown by EPR spectroscopy that they underwent clean homolysis of their N-O bonds upon UV photolysis. During photolysis of acetophenone O-allylcarbamoyl oxime, the corresponding oxazolidin-2-onylmethyl radical was detected by EPR spectroscopy, providing the first evidence that N-monosubstituted carbamoyloxyl radicals can hold their structural integrity. N,N-Disubstituted carbamoyloxyl radicals dissociated rapidly at the lowest accessible temperatures. Above room temperature, both types of oxime carbamate acted as selective new precursors for aminyl and iminyl radicals. Rate parameters were measured for 5-exo cyclization of N-benzyl-N-pent-4-enylaminyl radicals; the rate constant was smaller than for C-centered and O-centered analogues. Oxime carbamates derived from the volatile diethylamine afforded aryliminyl radicals that proved convenient for phenanthridine preparations.

Unconventional titania photocatalysis: direct deployment of carboxylic acids in alkylations and annulations.

Under dry, anaerobic conditions, TiO(2) photocatalysis of carboxylic acid precursors resulted in carbon-carbon bond-forming processes. High yields of dimers were obtained from TiO(2) treatment of carboxylic acids alone. On inclusion of electron-deficient alkenes, efficient alkylations were achieved with methoxymethyl and phenoxymethyl radicals. In reactions with maleic anhydride or maleimides, phenoxyacetic acid produced chromenedione derivatives in addition to adducts. These photocatalytic reactions are simple and cheap to perform, and the TiO(2) is easily removed by filtration. The anaerobic photocatalysis strategy offers a range of synthetic possibilities.

Pentameric circular iron(II) double helicates and a molecular pentafoil knot.

We report on the synthesis of 11 pentameric cyclic helicates formed by imine condensation of alkyl monoamines with a common bis(formylpyridine)bipyridyl-derived building block and iron(II) and chloride ions. The cyclic double-stranded helicates were characterized by NMR spectroscopy, mass spectrometry, and in the case of a 2,4-dimethoxybenzylamine-derived pentameric cyclic helicate, X-ray crystallography. The factors influencing the assembly process (reactant stoichiometry, concentration, solvent, nature and amount of anion) were studied in detail: the role of chloride in the assembly process appears not to be limited to that of a simple template, and larger circular helicates observed with related tris(bipyridine) ligands with different iron salts are not produced with the imine ligands. Using certain chiral amines, pentameric cyclic helices of single handedness could be isolated and the stereochemistry of the helix determined by circular dichroism. By employing a particular diamine, a closed-loop molecular pentafoil knot was prepared. The pentafoil knot was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography, confirming the topology and providing insights into the reasons for its formation.

A synthetic molecular pentafoil knot.

Knots are being discovered with increasing frequency in both biological and synthetic macromolecules and have been fundamental topological targets for chemical synthesis for the past two decades. Here, we report on the synthesis of the most complex non-DNA molecular knot prepared to date: the self-assembly of five bis-aldehyde and five bis-amine building blocks about five metal cations and one chloride anion to form a 160-atom-loop molecular pentafoil knot (five crossing points). The structure and topology of the knot is established by NMR spectroscopy, mass spectrometry and X-ray crystallography, revealing a symmetrical closed-loop double helicate with the chloride anion held at the centre of the pentafoil knot by ten CH···Cl(-) hydrogen bonds. The one-pot self-assembly reaction features an exceptional number of different design elements-some well precedented and others less well known within the context of directing the formation of (supra)molecular species. We anticipate that the strategies and tactics used here can be applied to the rational synthesis of other higher-order interlocked molecular architectures.

Strategies and tactics for the metal-directed synthesis of rotaxanes, knots, catenanes, and higher order links.

More than a quarter of a century after the first metal template synthesis of a [2]catenane in Strasbourg, there now exists a plethora of strategies available for the construction of mechanically bonded and entwined molecular level structures. Catenanes, rotaxanes, knots and Borromean rings have all been successfully accessed by methods in which metal ions play a pivotal role. Originally metal ions were used solely for their coordination chemistry; acting either to gather and position the building blocks such that subsequent reactions generated the interlocked products or by being an integral part of the rings or "stoppers" of the interlocked assembly. Recently the role of the metal has evolved to encompass catalysis: the metal ions not only organize the building blocks in an entwined or threaded arrangement but also actively promote the reaction that covalently captures the interlocked structure. This Review outlines the diverse strategies that currently exist for forming mechanically bonded molecular structures with metal ions and details the tactics that the chemist can utilize for creating cross-over points, maximizing the yield of interlocked over non-interlocked products, and the reactions-of-choice for the covalent capture of threaded and entwined intermediates.

UV promoted phenanthridine syntheses from oxime carbonate derived iminyl radicals.

Oxime carbonates were found to be excellent precursors for the clean and direct generation of iminyl radicals under UV irradiation. Suitably functionalised iminyls underwent cyclisations yielding various phenanthridines and also substituted quinolines and isoquinolines. EPR and X-ray analyses of oxime carbonates provided insight into the mechanism.

Improved dynamics and positional bias with a second generation palladium(II)-complexed molecular shuttle.

A second generation palladium(II)-complexed molecular shuttle, featuring structural changes to the size and shape of the macrocycle, shows significantly increased rates of shuttling and improved co-conformational bias compared to the original system.

Active metal template synthesis of rotaxanes, catenanes and molecular shuttles.

Active metal template synthesis is a powerful new strategy for the construction of rotaxanes, catenanes and other mechanically interlocked molecular structures. The key feature is that the metal plays a dual role during the assembly of the interlocked architecture, acting as both a template for entwining or threading the components and as a catalyst for capturing the interlocked final product by covalent bond formation. Unlike traditional "passive" metal template methods to rotaxanes and catenanes, permanent recognition motifs are not required on each of the components to be interlocked (i.e., the assembly can be traceless) and the template can often be used in sub-stoichiometric quantities. Since its inception in 2006, a rapidly growing number of different metal-catalysed reactions have proven suitable for the active metal template synthesis of both rotaxanes and catenanes, including the copper(i)-catalysed terminal alkyne-azide cycloaddition (the CuAAC "click" reaction), palladium- and copper-catalysed alkyne homocouplings and heterocouplings, and palladium-catalysed oxidative Heck couplings and Michael additions. In addition to simple rotaxanes and catenanes, the synthetic strategy has been used to construct switchable molecular shuttles with weak intercomponent interactions (a requirement for fast shuttling) and to provide insight into the mechanisms of transition metal-catalysed reactions. In this tutorial review we highlight the utility and potential of the early examples of the active metal template strategy in mechanically interlocked molecule synthesis.

Getting harder: cobalt(III)-template synthesis of catenanes and rotaxanes.

The synthesis of catenanes and rotaxanes using the hard trivalent transition metal ion cobalt(III) as a template is reported. Tridentate dianionic pyridine-2,6-dicarboxamido ligands, each with two terminal alkene groups, coordinate Co(III) in a mutually orthogonal arrangement such that entwined or interlocked molecular architectures are produced by ring-closing olefin metathesis. Double macrocyclization of two such ligands bound to Co(III) afford a non-interlocked "figure-of-eight" complex in 42% yield, the structure determined by X-ray crystallography. Preforming one macrocycle and carrying out a single macrocyclization of the second bis-olefin with both ligands attached to the Co(III) template led to the isomeric [2]catenate in 69% yield. The mechanically interlocked structure was confirmed by X-ray crystallography of both the Co(III) catenate and the metal-free catenand. A Co(III)-template [2]rotaxane was assembled in 61% yield by macrocyclization of the bis-olefin ligand about an appropriate dianionic thread. For both catenanes and rotaxanes, removal of the metal ion via reduction under acidic conditions to the more labile Co(II) gave neutral interlocked molecules with well-defined co-conformations stabilized by intercomponent hydrogen bonding.