B(C6F5)3-Catalyzed Dehydrogenation of Pyrrolidines to Form Pyrroles.

Pyrroles are important N-heterocycles found in medicines and materials. The formation of pyrroles from widely accessible pyrrolidines is a potentially attractive strategy but is an underdeveloped approach due to the sensitivity of pyrroles to the oxidative conditions required to achieve such a transformation. Herein, we report a catalytic approach that employs commercially available B(C6F5)3 in an operationally simple procedure that allows pyrrolidines to serve as direct synthons for pyrroles. Mechanistic studies have revealed insights into borane-catalyzed dehydrogenative processes.

An immunogenic anti-cancer stem cell bi-nuclear copper(II)-flufenamic acid complex.

An asymmetric bi-nuclear copper(II) complex with both cytotoxic and immunogenic activity towards breast cancer stem cells (CSCs) is reported. The bi-nuclear copper(II) complex comprises of two copper(II) centres bound to flufenamic acid and 3,4,7,8-tetramethyl-1,10-phenanthroline. The bi-nuclear copper(II) complex exhibits sub-micromolar potency towards breast CSCs grown in monolayers and three-dimensional cultures. Remarkably, the bi-nuclear copper(II) complex is up to 25-fold more potent toward breast CSC mammospheres than salinomycin (a gold standard anti-breast CSC agent) and cisplatin (a clinically administered metallodrug). Mechanistic studies showed that the bi-nuclear copper(II) complex readily enters breast CSCs, elevates intracellular reactive oxygen species levels, induces apoptosis, and promotes damage-associated molecular pattern release. The latter triggers phagocytosis of breast CSCs by macrophages. As far as we are aware, this is the first report of a bi-nuclear copper(II) complex to induce engulfment of breast CSCs by immune cells.

Metal-carbon bonding in early lanthanide substituted cyclopentadienyl complexes probed by pulsed EPR spectroscopy.

We examine lanthanide (Ln)-ligand bonding in a family of early Ln3+ complexes [Ln(Cptt)3] (1-Ln, Ln = La, Ce, Nd, Sm; Cptt = C5H3tBu2-1,3) by pulsed electron paramagnetic resonance (EPR) methods, and provide the first characterization of 1-La and 1-Nd by single crystal XRD, multinuclear NMR, IR and UV/Vis/NIR spectroscopy. We measure electron spin T1 and Tm relaxation times of 12 and 0.2 µs (1-Nd), 89 and 1 µs (1-Ce) and 150 and 1.7 µs (1-Sm), respectively, at 5 K: the T1 relaxation of 1-Nd is more than 102 times faster than its valence isoelectronic uranium analogue. 13C and 1H hyperfine sublevel correlation (HYSCORE) spectroscopy reveals that the extent of covalency is negligible in these Ln compounds, with much smaller hyperfine interactions than observed for equivalent actinide (Th and U) complexes. This is corroborated by ab initio calculations, confirming the predominant electrostatic nature of the metal-ligand bonding in these complexes.

The Anti-Breast Cancer Stem Cell Potency of Copper(I)-Non-Steroidal Anti-Inflammatory Drug Complexes.

Cancer stem cells (CSCs) are thought to be partly responsible for metastasis and cancer relapse. Currently, there are no effective therapeutic options that can remove CSCs at clinically safe doses. Here, we report the synthesis, characterisation, and anti-breast CSC properties of a series of copper(I) complexes, comprising of non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine ligands (1-3). The copper(I) complexes are able to reduce the viability of breast CSCs grown in two- and three-dimensional cultures at micromolar concentrations. The potency of the copper(I) complexes towards breast CSCs was similar to salinomycin (an established anti-breast CSC agent) and cisplatin (a clinically used metallopharmaceutical). Cell-based studies showed that the copper(I) complexes are readily, and similarly, internalised by breast CSCs. The copper(I) complexes significantly increase the intracellular reactive oxygen species (ROS) levels in breast CSCs, and their ROS generation profile with respect to time is dependent on the NSAID component present. The generation of intracellular ROS by the copper(I) complexes could be part of the underlying mechanism by which they evoke breast CSC death. As far as we are aware, this is the first study to explore the anti-breast CSC properties of copper(I) complexes.

A Blueprint for the Stabilization of Sub-Valent Alkaline Earth Complexes.

The study of sub-valent Group 2 chemistry is a relatively new research field, being established in 2007 with the report of the first Mg(I) dimers. These species are stabilized by the formation of a Mg-Mg covalent bond; however, the extension of this chemistry to heavier alkaline earth (AE) metals has been frustrated by significant synthetic challenges, primarily associated with the instability of heavy AE-AE interactions. Here we present a new blueprint for the stabilization of heavy AE(I) complexes, based upon the reduction of AE(II) precursors with planar coordination geometries. We report the synthesis and structural characterisation of homoleptic trigonal planar AE(II) complexes of the monodentate amides {N(SiMe3 )2 }- and {N(Mes)(SiMe3 )}- . DFT calculations showed that the LUMOs of these complexes all show some d-character for AE = Ca-Ba. DFT analysis of the square planar Sr(II) complex [Sr{N(SiMe3 )2 }(dioxane)2 ]∞ revealed analogous frontier orbital d-character. AE(I) complexes that could be accessed by reduction of these AE(II) precursors were modelled computationally, revealing exergonic formation in all cases. Crucially, NBO calculations show that some d-character is preserved in the SOMO of theoretical AE(I) products upon reduction, showing that d-orbitals could play a crucial role in achieving stable heavy AE(I) complexes.

The Bulk Breast Cancer Cell and Breast Cancer Stem Cell Activity of Binuclear Copper(II)-Phenanthroline Complexes.

Mononuclear copper(II)-phenanthroline complexes have been widely investigated as anticancer agents whereas multinuclear copper(II)-phenanthroline complexes are underexplored. Here the synthesis and characterisation of two new binuclear copper(II)-phenanthroline complexes 1 and 2 is reported, comprising of 2,9-dimethyl-1,10-phenanthroline or 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, terminal chloride ligands, and bridging chloride or hydroxide ligands. The binuclear copper(II) complex containing 2,9-dimethyl-1,10-phenanthroline 1 displays nanomolar toxicity towards bulk breast cancer cells and breast cancer stem cells (CSCs) grown in monolayers, >50-fold greater than cisplatin (an anticancer metallodrug) and salinomycin (a gold-standard anti-CSC agent). Spectacularly, 1 exhibits >100-fold greater potency toward three-dimensionally cultured mammospheres than cisplatin and salinomycin. Mechanistic studies show that 1 evokes breast CSC apoptosis by elevating intracellular reactive oxygen species levels and damaging genomic DNA (possibly by an oxidative mechanism). To the best of our knowledge, this is the first study to probe the anti-breast CSC properties of binuclear copper(II)-phenanthroline complexes.

Synthesis and characterization of two self-assembled [Cu6Gd3] and [Cu5Dy2] complexes exhibiting the magnetocaloric effect, slow relaxation of magnetization, and anticancer activity.

Two new paths for coordination driven self-assembly reactions under the binding support of 2-((1-hydroxy-2-methylpropan-2-ylimino)methyl)-6-methoxyphenol (H2L) have been discovered from the reactions of Cu(ClO4)2·6H2O, NEt3 and GdCl3/DyCl3·6H2O in MeOH/CHCl3 (2 : 1) medium. A similar synthetic protocol is useful to provide two different types of self-aggregated molecular clusters [Cu6Gd3(L)3(HL)3(µ3-Cl)3(µ3-OH)6(OH)2]ClO4·4H2O (1) and [Cu5Dy2(L)2(HL)2(µ-Cl)2(µ3-OH)4(ClO4)2(H2O)6](ClO4)2·2NHEt3Cl·21H2O (2). The adopted reaction procedure established the importance of the HO- and Cl- ions in the mineral-like growth of the complexes, derived from solvents and metal ion salts. In the case of complex 1, one GdIII center has been trapped at the central position of the core upheld by six µ3-OH and three µ3-Cl groups, whereas for complex 2 one CuII center was trapped using four µ3-hydroxo and two µ-chlorido groups. The magnetothermal behavior of 1 has been examined for a magnetocaloric effect of -ΔSm = 11.3 J kg-1 K-1 at 2 K for ΔH = 7 T, whereas the magnetic susceptibility measurements of 2 showed slow magnetic relaxation with Ueff = 15.8 K and τ0 = 9.8 × 10-7 s in zero external dc field. Cancer cell growth inhibition studies proved the potential of both the complexes with interestingly high activity for the Cu6Gd3 complex against human lung cancer cells. Both complexes 1 and 2 also exhibited DNA and human serum albumin (HSA) binding abilities in relation to the involved binding sites and thermodynamics.

Synthesis, characterisation and reactivity of group 2 complexes with a thiopyridyl scorpionate ligand.

Herein we report the reactivity of the proligand tris(2-pyridylthio)methane (HTptm) with various Alkaline Earth (AE) reagents: (1) dialkylmagnesium reagents and (2) AE bis-amides (AE = Mg-Ba). Heteroleptic complexes of general formulae [Mg(Tptm)(R)] (R = Me, nBu; Tptm = {C(S-C5H4N)3}-) and [AE(Tptm)(N'')] (AE = Mg-Ba; N'' = {N(SiMe3)2}-) were targeted from the reaction of HTptm with R2Mg or [AE(N'')2]2. Reaction of the proligand with dialkylmagnesium reagents led to formation of [{Mg(κ3C,N,N-C{Bu}{S-C5H4N}2)(µ-S-C5H4N)}2] (1) and [{Mg(κ3C,N,N-C{Me}{S-C5H4N}2)(µ-OSiMe3)}2] (2) respectively, as a result of a novel transfer of an alkyl group onto the methanide carbon with concomitant C-S bond cleavage. However, reactivity of bis-amide precursors for Mg and Ca did afford the target species [AE(Tptm)(N'')] (3-AE; AE = Mg-Ca), although these proved susceptible to ligand degradation processes. DFT calculations show that alkyl transfer in the putative [Mg(Tptm)(nBu)] (1m') system and amide transfer in 3-Ca is a facile process that induces C-S bond cleavage in the Tptm ligand. 3-Mg and 3-Ca were also tested as catalysts for the hydrophosphination of selected alkenes and alkynes, including the first example of mono-hydrophosphination of 4-ethynylpyridine which was achieved with high conversions and excellent regio- and stereochemical control.

Structural Investigation of Magnesium Complexes Supported by a Thiopyridyl Scorpionate Ligand.

Herein, we report the synthesis of a series of heteroleptic magnesium complexes stabilized with the scorpionate ligand tris(2-pyridylthio)methanide (Tptm). The compounds of the general formula [Mg(Tptm)(X)] (1-X; X = Cl, Br, I) were obtained via protonolysis reaction between the proligand and selected Grignard reagents. Attempts to isolate the potassium derivative K(Tptm) lead to decomposition of Tptm and formation of the alkene (C5H4N-S)2C=C(C5H4N-S)2, and this degradation was also modelled using DFT methods. Compound 1-I was treated with K(CH2Ph), affording the degradation product [Mg(Bptm)2] (2; Bptm = {CH(S-C5NH3)2}-). We analyzed and quantified the steric properties of the Tptm ligand using the structural information of the compounds obtained in this study paired with buried volume calculations, also adding the structural data of HTptm and its CF3-substituted congener (HTptmCF3). These studies highlight the highly flexible nature of this ligand scaffold and its ability to stabilize various coordination motifs and geometries, which is a highly desirable feature in the design of novel organometallic reagents and catalysts.

A bioinspired redox-modulating copper(II)-macrocyclic complex bearing non-steroidal anti-inflammatory drugs with anti-cancer stem cell activity.

Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from in vitro studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex 1 comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of 1 is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that 1 kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that 1 is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that 1 evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)-NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates.

Rare Earth Starting Materials and Methodologies for Synthetic Chemistry.

The number of rare earth (RE) starting materials used in synthesis is staggering, ranging from simple binary metal-halide salts to borohydrides and "designer reagents" such as alkyl and organoaluminate complexes. This review collates the most important starting materials used in RE synthetic chemistry, including essential information on their preparations and uses in modern synthetic methodologies. The review is divided by starting material category and supporting ligands (i.e., metals as synthetic precursors, halides, borohydrides, nitrogen donors, oxygen donors, triflates, and organometallic reagents), and in each section relevant synthetic methodologies and applications are discussed.

Photoluminescence of Pentavalent Uranyl Amide Complexes.

Pentavalent uranyl species are crucial intermediates in transformations that play a key role for the nuclear industry and have recently been demonstrated to persist in reducing biotic and abiotic aqueous environments. However, due to the inherent instability of pentavalent uranyl, little is known about its electronic structure. Herein, we report the synthesis and characterization of a series of monomeric and dimeric, pentavalent uranyl amide complexes. These synthetic efforts enable the acquisition of emission spectra of well-defined pentavalent uranyl complexes using photoluminescence techniques, which establish a unique signature to characterize its electronic structure and, potentially, its role in biological and engineered environments via emission spectroscopy.

Synthesis and characterization of new Pd(ii) and Pt(ii) complexes with 3-substituted 1-(2-pyridyl)imidazo[1,5-a]pyridine ligands.

Several palladium(ii) and platinum(ii) complexes (1-20) of general formula [M(Ln)(X)(Y)] [M = Pd, X = Y = Cl (1-Cl-4-Cl), X = Y = OAc (1-OAc-4-OAc); M = Pt: X = Y = Cl (5-8); M = Pd, X = Cl, Y = CH3 (9-12); M = Pt, X = Cl, Y = CH3 (13-16) or X = Y = CH3 (17-20); n = 1-4] have been synthesized by reaction of different Pd(ii) and Pt(ii) derivatives with various 3-substituted 1-(2-pyridyl)-imidazo[1,5-a]pyridines; i.e.Ln = 1-(2-pyridyl)-3-arylimidazo[1,5-a]pyridine (aryl = Phenyl, L1; 2-o-Tolyl, L2; Mesityl, L3) and 1-(2-pyridyl)-3-benzylimidazo[1,5-a]pyridine (L4). Detailed spectroscopic investigation (including IR, mono- and bi-dimensional 1H NMR) and elemental analysis has been performed for all these species, allowing their complete characterization. Ln act as N,N-bidentate ligands and coordinate the metal centers in a chelate fashion through the pyridyl (Npy) and the pyridine-like nitrogen atom of the imidazo[1,5-a]pyridine group (Nim). The X-ray structural analysis performed on two of Pd(ii) and three Pt(ii) complexes, namely [Pd(L2)(CH3)Cl] (10), [Pd(L3)(CH3)Cl] (11) and [Pt(L1)Cl2] (5), [Pt(L4)Cl2] (8), [Pt(L2)(CH3)Cl] (14) confirmed the spectroscopic and analytical data. Finally DFT studies unveiled the structural reasons behind the inertia of the synthesised compounds toward metalation, identified as the higher angle steric strain in comparison with the analogous bipyridine complexes.

Dimerized p-Semiquinone Radical Anions Stabilized by a Pair of Rare-Earth Metal Ions.

Here we report stable p-quinone-radical-bridged rare-earth complexes involving the ligand tetramethylquinone (QMe4•-). The complexes, {Y[(QMe4)•-Cl2(THF)3]}2 (1) and {Gd[(QMe4)•-Cl2(THF)3]}2 (2), where THF = tetrahydrofuran, are sufficiently stable that we can measure the single-crystal structures and perform magnetic and electron paramagnetic resonance measurements. These studies show the presence of a semiquinone form and that the magnetic interaction between the radicals in the dimer is strong and antiferromagnetic.

Synthesis and characterisation of light lanthanide bis-phospholyl borohydride complexes.

Organometallic lanthanide (Ln) chemistry is dominated by complexes that contain substituted cyclopentadienyl (CpR) ligands. Closely related phospholyls have received less attention, and although they have proven utility in stabilising low oxidation state Ln complexes the trivalent Ln chemistry of these ligands is limited in comparison. Herein, we synthesise two families of heteroleptic Ln3+ complexes, [Ln(Htp)2(µ-BH4)]2 (Htp = 2,5-di-tert-butylphospholyl; 1-Ln; Ln = La, Ce, Nd, Sm), and [[Ln(Htp)2(µ-BH4)2K(S)]n (2-Ln, Ln = La, Ce, S = 2 DME, n = 2; 3-Ce, Ln = Ce, S = Et2O and THF, n = ∞) via the reactions of parent [Ln(BH4)3(THF)3.5] with K(Htp), to investigate differences between Ln complexes with substituted phospholyl ligands and analogous CpR complexes. Complexes 1-3-Ln were characterised as appropriate by single crystal XRD, SQUID magnetometry, elemental analysis, multinuclear NMR, ATR-IR and UV-Vis-NIR spectroscopy. Ab initio calculations reveal that small changes in the Ln3+ coordination spheres of these complexes can have relatively large influences on crystal field splitting.

A double-dysprosocenium single-molecule magnet bound together with neutral ligands.

A dinuclear dysprosocenium dication has been synthesised that is bound together by weak interactions between {Dy(Cp*)2}+ fragments and neutral NEt3AlMe3 molecules. The axiality of the Dy3+ crystal fields are perturbed by these equatorial interactions but a relatively large effective barrier to magnetisation reversal of 860(60) cm-1 and magnetic hysteresis up to 12 K are observed.

Probing Relaxation Dynamics in Five-Coordinate Dysprosium Single-Molecule Magnets.

A new family of five-coordinate lanthanide single-molecule magnets (Ln SMMs) [Dy(Mes*O)2 (THF)2 X] (Mes*=2,4,6-tri-tert-butylphenyl; X=Cl, 1; Br, 2; I, 3) is reported with energy barriers to magnetic reversal >1200 K. The five-coordinate DyIII ions have distorted square pyramidal geometries, with halide anions on the apex, and two Mes*O ligands mutually trans- to each other, and the two THF molecules forming the second trans- pair. These geometrical features lead to a large magnetic anisotropy in these complexes along the trans-Mes*O direction. QTM and Raman relaxation times are enhanced by varying the apex halide from Cl to Br to I, or by dilution in a diamagnetic yttrium analogue.

Studies of hysteresis and quantum tunnelling of the magnetisation in dysprosium(iii) single molecule magnets.

We report magnetic hysteresis studies of three Dy(iii) single-molecule magnets (SMMs). The three compounds are [Dy(tBuO)Cl(THF)5][BPh4] (1), [K(18-crown-6-ether)(THF)2][Dy(BIPM)2] (2, BIPM = C{PPh2NSiMe3}2), and [Dy(Cpttt)2][B(C6F5)4] (3), chosen as they have large energy barriers to magnetisation reversal of 665, 565, and 1223 cm-1, respectively. There are zero-field steps in the hysteresis loops of all three compounds, that remain in magnetically dilute samples and in samples that are isotopically enriched with 164Dy, which has no nuclear spin. These results demonstrate that neither dipolar fields nor nuclear hyperfine coupling are solely responsible for the quantum tunnelling of magnetisation at zero field. Analysing their vibrational modes, we find that the modes that most impact the first coordination sphere occur at the lowest energies for 1, at intermediate energies for 2 and at higher energies for 3, in correlation with their coercive fields. Therefore, we suggest that the efficiency of quantum tunnelling of magnetisation is related to molecular flexibility.

Light Lanthanide Metallocenium Cations Exhibiting Weak Equatorial Anion Interactions.

As the dysprosocenium complex [Dy(Cpttt )2 ][B(C6 F5 )4 ] (Cpttt =C5 H2 tBu3 -1,2,4, 1-Dy) exhibits magnetic hysteresis at 60 K, similar lanthanide (Ln) complexes have been targeted to provide insights into this remarkable property. We recently reported homologous [Ln(Cpttt )2 ][B(C6 F5 )4 ] (1-Ln) for all the heavier Ln from Gd-Lu; herein, we extend this motif to the early Ln. We find, for the largest LnIII cations, that contact ion pairs [Ln(Cpttt )2 {(C6 F5 -κ1 -F)B(C6 F5 )3 }] (1-Ln; La-Nd) are isolated from reactions of parent [Ln(Cpttt )2 (Cl)] (2-Ln) with [H(SiEt3 )2 ][B(C6 F5 )4 ], where the anion binds weakly to the equatorial sites of [Ln(Cpttt )2 ]+ through a single fluorine atom in the solid state. For smaller SmIII , [Sm(Cpttt )2 ][B(C6 F5 )4 ] (1-Sm) is isolated, which like heavier 1-Ln does not exhibit equatorial anion interactions, but the EuIII analogue 1-Eu could not be synthesised due to the facile reduction of EuIII precursors to EuII products. Thus with the exception of Eu and radioactive Pm this work constitutes a structurally similar family of Ln metallocenium complexes, over 50 years after the [M(Cp)2 ]+ series was isolated for the 3d metals.

New Variations on the Theme of Gold(III) C∧N∧N Cyclometalated Complexes as Anticancer Agents: Synthesis and Biological Characterization.

A series of novel (C∧N∧N) cyclometalated AuIII complexes of general formula [Au(bipydmb-H)X][PF6] (bipydmb-H = C∧N∧N cyclometalated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine) were prepared with a range of anionic ligands X in the fourth coordination position, featuring C (alkynyl)-, N-, O-, or S-donor atoms. The X ligands are varied in nature and include three coumarins, 4-ethynylaniline, saccharine, and thio-ß-d-glucose tetraacetate, the tripeptide glutathione (GSH), and a coumarin-substituted amide derived from 4-ethynylaniline. The gold(I) complex [Au(C2ArNHCOQ)(PPh3)] (HC2ArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2 H-chromene-3-carboxamide) was also prepared for comparison. The new compounds were fully characterized by means of analytical techniques, including NMR, absorption, and emission spectroscopy. The crystal structures of three cyclometalated AuIII complexes and of the AuI derivative were solved by single-crystal X-ray diffraction. The antiproliferative activity of the new AuIII cyclometalated derivatives was evaluated against cancer cells in vitro. According to the obtained results, only complexes 3-PF6 and 5-PF6, featuring coumarins as ancillary ligands and endowed with high redox stability in solution, display antiproliferative effects, with 5-PF6 being the most potent, while all of the others are scarcely active to nonactive in the selected cell lines. In order to study the reactivity of the compounds with biomolecules, the interaction of complexes 3-PF6 and 5-PF6 with the protein cytochrome c and the amino acids cysteine and histidine was analyzed by electrospray ionization mass spectrometry (ESI MS), showing adduct formation only with Cys after at least 1 h incubation. Furthermore, the parent hydroxo complex [Au(bipydmb-H)(OH)][PF6] (1OH-PF6) was investigated in a competitive assay to determine the protein vs oligonucleotide binding preferences by capillary zone electrophoresis (CZE) coupled to ESI-MS. Of note, the compound was found to selectively form adducts with the oligonucleotide over the protein upon ligand exchange with the hydroxido ligand. Adduct formation occurred within the first 10 min of incubation, demonstrating the preference of 1OH-PF6 for nucleotides in this setup. Overall, the obtained results point toward the possibility to selectively target DNA with gold(III) organometallics.