Iridium Complexes with Bidentate Pyridinylidene/N-Amidate Ligands for Transfer Hydrogenation Catalysis.

A series of iridium pentamethylcyclopentadienyl (Cp*) complexes, [Cp*Ir(κ2-RLp/m)Cl], that contain the strongly coordinating bidentate ligands RLp/m were synthesized. The donor groups of the bidentate ligands were an N-amidate and either a para-pyridinylidene remote N-heterocyclic carbene (RLp) or a meta-pyridinylidene remote N-heterocyclic carbene (RLm). For each type of bidentate ligand, a set of iridium complexes was synthesized, which differed only according to the substituents (R) on the phenyl ring associated with the amidate group. The iridium complexes were all fully characterized and molecular structures were obtained by single-crystal X-ray diffraction studies for representative examples. The complexes were found to be good precatalysts in iso-propanol for the transfer hydrogenation of benzaldehyde to give benzyl alcohol. The catalytic activity correlated with the Hammett σm/p parameters of the phenyl ring substituents, with more electron-donating substituents leading to increased catalytic activity. In all cases, the meta-pyridinylidene complexes, [Cp*Ir(κ2-RLm)Cl], performed better than the corresponding para analogues, [Cp*Ir(κ2-RLp)Cl].

An Iron Macrocyclic Complex Containing Four "Hybrid" Pyridinium Amidate/Amidate N-Donors as a Catalyst for Oxidations with Hydrogen Peroxide.

The macrocyclic proligand [H4 L][OTf]2 , which contains four carboxamide functions and two conjugated pyridinium groups, is easily deprotonated by the weak base sodium acetate to give the corresponding neutral proligand [H2 L]. Metallation of [H2 L] with iron(II) chloride proceeds rapidly to form the macrocyclic complex, [FeIII Cl(L)]. This is an effective catalyst for the oxidation of the organic dye orange II by hydrogen peroxide in aqueous solution, and the kinetic parameters for this reaction have been determined. In striking contrast to an analogous iron-TAML complex that contains two phenyl groups in place of the two pyridinium groups, [FeIII Cl(L)] is a very active oxidation catalyst at pH 7 and is also highly stable towards acid-promoted demetallation at pH 5 or above. The results show that the two pyridinium groups bring greatly enhanced catalytic properties to [FeIII Cl(L)].

Ferrocene-Derived Palladium(II)-Based Metallosupramolecular Structures: Synthesis, Guest Interaction, and Stimulus-Responsiveness Studies.

Using ferrocene-based ligand systems, a series of heterobimetallic architectures of the general formula [PdmLn]x+ were designed with the aim of installing an opening and closing mechanism that would allow the release and binding of guest molecules. Palladium complex formation was achieved through coordination to pyridyl groups, and using 2-, 3-, and 4-pyridyl derivatives provided access to defined PdL, PdL2, and Pd2L4 structures, respectively. The supramolecular complexes were characterized using nuclear magnetic resonance (NMR) and infrared spectroscopy, mass spectrometry, and elemental analysis, and for some examples density functional theory calculations and single-crystal X-ray diffraction analysis. 1H NMR spectroscopy was used to investigate disassembly and reassembly of the metallosupramolecular structures. The former was induced by cleavage of the relatively labile Pd-Npyridyl bonds with the introduction of the competing ligands N,N'-dimethylaminopyridine (DMAP) and Cl- (using tetrabutylammonium chloride) to yield [Pd(DMAP)4]2+ and [PdCl4]2-, respectively. The process was found to be reversible for several of the heterodimetallic compounds, with the addition of H+ or Ag+ triggering complex reassembly. Guest binding studies with several architectures revealed interactions with the anionic guests p-toluenesulfonate and octyl sulfate, but not with neutral molecules. Furthermore, the release of guests was reversibly induced with Cl- ions as a stimulus.

Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding.

A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pdn Ptm L4 ]6+ (DC1: n=1, m=2; and DC2: n=2, m=1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions. 1 H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1, which features two identical cavities, binding two 2,6-diaminoanthraquinone (DAQ) guest molecules was determined by single-crystal X-ray crystallography. In addition, DC1 was shown to bind two molecules of 5-fluorouracil (5-FU) in a statistical (non-cooperative) manner. In contrast, DC2, which features two different cage cavities, was found to interact with two different guests, 5-FU and cisplatin, selectively.

Quantification and composition of pharmaceutical waste in New Zealand.

This study aimed to quantify the amount of pharmaceutical waste produced in New Zealand, and determine the composition of pharmaceutical waste from community pharmacies in Auckland, New Zealand. Pharmaceutical waste collected in New Zealand is increasing, peaking at 542 tonne in 2019. Pharmaceutical waste collected from hospitals and pharmacies in Auckland increased by more than fourfold from 2016 to 2020. An audit of the types of pharmaceutical waste collected from community pharmacies revealed that the most common classes of drugs identified in this waste stream belonged to the nervous system, cardiovascular system and alimentary tract, and metabolism. Following examination of the contents of 12 pharmaceutical waste bins, 475 different pharmaceutical products were identified, highlighting the breadth of drugs in this waste stream. A range of dosage forms and hence materials were identified, which could present challenges for future waste treatment approaches. Hazardous drugs were identified including cytotoxic compounds, which should go into a separate waste stream for incineration. There is a need for similar data to be collected from multiple sites to fully appreciate the magnitude and composition of pharmaceutical waste. This will allow for the suitability of current practices for managing this hazardous waste stream to be evaluated.

Carbon Monoxide is an Inhibitor of HIF Prolyl Hydroxylase Domain 2.

Hypoxia-inducible factor prolyl hydroxylase domain 2 (PHD2) is an important oxygen sensor in animals. By using the CO-releasing molecule-2 (CORM-2) as an in situ CO donor, we demonstrate that CO is an inhibitor of PHD2. This report provides further evidence about the emerging role of CO in oxygen sensing and homeostasis.

A Reduced-Symmetry Heterobimetallic [PdPtL4 ]4+ Cage: Assembly, Guest Binding, and Stimulus-Induced Switching.

A strategy is presented that enables the quantitative assembly of a heterobimetallic [PdPtL4 ]4+ cage. The presence of two different metal ions (PdII and PtII ) with differing labilities enables the cage to be opened and closed selectively at one end upon treatment with suitable stimuli. Combining an inert PtII tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions led to the assembly of the cage. 1 H and DOSY NMR spectroscopy and ESI mass spectrometry data were consistent with the quantitative formation of the cage, and the heterobimetallic structure was confirmed using single-crystal X-ray crystallography. The structure of the host-guest adduct with a 2,6-diaminoanthraquinone guest molecule was determined. Addition of N,N'-dimethylaminopyridine (DMAP) resulted in the formation of the open-cage [PtL4 ]2+ compound and [Pd(DMAP)4 ]2+ complex. This process could then be reversed, with the reformation of the cage, upon addition of p-toluenesulfonic acid (TsOH).

Recent Advances in Metallaaromatic Chemistry.

Metallaaromatics can be broadly defined as aromatic compounds in which one of the ring atoms is a transition metal. The metallabenzenes are one important class of these compounds that has undergone extensive study recently. Closely related species such as fused-ring metallabenzenes, heterometallabenzenes, π-coordinated metallabenzenes and metallabenzynes have also attracted considerable attention. Although many metallaaromatics can be considered as metalla-analogues of classic organic aromatic compounds, this is not always the case. Recent seminal studies have shown that metallapentalenes and metallapentalynes, which are metalla-analogues of the anti-aromatic compounds pentalene and pentalyne, are in fact aromatic and highly stable. Very unusual spiro-metallaaromatic compounds have also recently been isolated. In this concepts article, key features of all these intriguing metallaaromatic compounds are discussed with reference to the structural, spectroscopic, reactivity and theoretical studies that have been undertaken. These compounds continue to generate much interest, not only because of the contributions they make to fundamental chemical understanding, but also because of the promise of possible practical applications.

Syntheses of Amino-Substituted Iridabenzofurans and Subsequent Selective N-Functionalisation.

The first examples of amino-substituted fused-ring metallabenzenes, the cationic iridabenzofuran [Ir(C7 H4 O{NH2 -2}{OMe-7})(CO)(PPh3 )2 ][O3 SCF3 ] (5) and neutral analogue Ir(C7 H4 {NH2 -2}{OMe-7})Cl(PPh3 )2 (6), can be prepared by reduction of the corresponding nitro-substituted iridabenzofurans with zinc and concentrated hydrochloric acid. N-functionalised derivatives of 5 and 6 are formed through alkylation, sulfonylation or acylation. Thus, consecutive treatments with methyl triflate and base gives the corresponding trimethylammonium-substituted iridabenzofurans while sulfonamide derivatives are formed with p-toluenesulfonyl chloride. N-Acylation of 5 or 6 with acid chlorides, however, selectively form either amide or imide products depending on the charge on the metal and the steric size of the acid chloride. Cationic 5 gives amide substituted products regardless of the conditions whereas neutral 6 rapidly undergoes di-N-acylation with excess benzoyl chloride under mild conditions to give the imide-substituted product Ir(C7 H4 O{N[C(O)Ph]2 -2}{OMe-7})Cl(PPh3 )2 (13). Selective mono-acylation of 6 can be achieved with one equivalent of benzoyl chloride or with excess of the sterically congested pivaloyl chloride.

A Metallaanthracene and Derived Metallaanthraquinone.

Metalla-analogues of archetypal aromatic molecules are attracting ever increasing interest. Although metallabenzenes (which fall within this class) have been well studied, fused-ring metallabenzenes are rare and of the linear polycyclic metallaaromatic hydrocarbons, only metallanaphthalene is known. Herein we report the first metallaanthracene, [Ir(C13 H8 {CH2 CO2 Me-5})Cl(PPh3 )2 ]O3 SCF3 (5), which represents the next member of this series of polycyclic compounds. Structurally, 5 has a number of features in common with anthracene including fused-ring planarity and bond-length alternation. In analogues of classic reactions of anthracene, 5 forms a Diels-Alder adduct with maleic anhydride and on oxidation the unprecedented fused-ring metallaanthraquinone, [Ir(C15 H6 O{Br-6}{OMe-7}{=O-8}{=O-15})Br(PPh3 )2 ], is obtained.

Solvent-dependent switch of ligand donor ability and catalytic activity of ruthenium(II) complexes containing pyridinylidene amide (PYA) N-heterocyclic carbene hybrid ligands.

Chelating ligands incorporating both N-[1-alkylpyridin-4(1H)-ylidene]amide (PYA) and N-heterocyclic carbene (NHC) donor sites were prepared and used for the synthesis of ruthenium(II) complexes. Cyclic voltammetry, NMR, and UV-vis spectroscopy of the complexes indicate a solvent-dependent contribution of the limiting resonance structures associated with the ligand in solution. The neutral pyridylidene imine structure is more pronounced in apolar solvents (CH2Cl2), while the mesoionic pyridinium amide form is predominant in polar solvents (MeOH, DMSO). The distinct electronic properties of these hybrid PYA-NHC ligands in different solvents have a direct influence on the catalytic activity of the ruthenium center, e.g., in the dehydrogenation of benzyl alcohol to benzaldehyde. The activity in different solvents qualitatively correlates with the solvent permittivity.

A dynamic covalent approach to [PtnL2n]2n+ cages.

A dynamic covalent approach was exploited to generate a family of homometallic [PtnL2n]2n+ cage (predominantly [Pt2L4]4+ systems) architectures. The family of platinum(II) architectures were characterized using 1H nuclear magnetic resonance (NMR) and diffusion ordered spectroscopy (DOSY), electrospray ionization mass spectrometry (ESI-MS) and the molecular structures of two cages were determined by X-ray crystallography.

Exploiting reduced-symmetry ligands with pyridyl and imidazole donors to construct a second-generation stimuli-responsive heterobimetallic [PdPtL4]4+ cage.

A new sequential metalation strategy that enables the assembly of a new more robust reduced symmetry heterobimetallic [PdPtL4]4+ cage C is reported. By exploiting a low-symmetry ditopic ligand (L) that features imidazole and pyridine donor units we were able to selectively form a [Pt(L)4]2+ "open-cage" complex. When this was treated with Pd(ii) ions the cage C assembled. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the quantitative formation of the cage and the heterobimetallic structure was confirmed by single crystal X-ray crystallography. The cage C was shown to bind anionic guest molecules. NMR studies suggested that these guests interacted with the cavity of the cage in a specific orientation and this was confirmed for the mesylate ion (MsO-) : C host-guest adduct using X-ray crystallography. In addition, the system was shown to be stimulus-responsive and could be opened and closed on demand when treated with appropriate stimuli. If a guest molecule was bound within the cage, the opening and closing was accompanied by the release and re-uptake of the guest molecule.

Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host-guest chemistry.

A new [PdPtL4]4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL4]4+ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p-tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL4]4+ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host-guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD3CN. No HG interactions were observed in the more polar d6-DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC50) values in the range of 25-35 µM. Most [PdPtL4]4+-drug mixtures tested had higher IC50 values than the hosts. However, the [PdPtL4]4+ cages, and [PdPtL4]4+:drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil.

Redox-controlled, reversible rearrangement of a tris(2-pyridylthio)methyl ligand on nickel to an isomer with an "N,S-confused" 2-pyridylthiolate arm.

Interchange between the nickel +2 and +3 oxidation states precisely controls the reversible rearrangement of the tris(2-pyridylthio)methanide (tptm) ligand in the organometallic nickel(II) complex [{Ni(µ-Br)-(tptm)}(2)] (2). Oxidation of 2 first gives the corresponding Ni(III) complex [{Ni(µ-Br)(tptm)}(2)][PF(6)](2) (4). However, in solution the tptm ligand in 4 slowly undergoes a rearrangement, in which the N and S atoms of one of the pyridylthiolate arms exchange Ni and C bonding partners, thereby resulting in an "N,S-confused" isomer of tptm in the product, [NiBr(bpttpm)]PF(6) (5; bpttpm= bis(2-pyridylthio)(2-thiopyridinium)-methyl). Reduction of 5 reverses this ligand rearrangement and 2 is reformed quantitatively. The individual steps involved in these unusual ligand rearrangements were investigated by a number of methods, including voltammetric analysis, and a mechanism for this process is proposed. X-ray crystal structure determinations of the key compounds 2, 4 and 5 have been obtained.

Extending the range of neutral N-donor ligands available for metal catalysts: N-[1-alkylpyridin-4(1H)-ylidene]amides in palladium-catalyzed cross-coupling reactions.

N-[1-Alkylpyridin-4(1H)-ylidene]amides (PYAs) are a new class of easily prepared, neutral N-donor ligands that share some features in common with N-heterocyclic carbenes. They are strongly electron-donating toward metal centers, and a palladium(II) complex of one of these ligands has been shown to successfully catalyze both the Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions.

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity.

Two new di(2,2'-bipyridine) ligands, 2,6-bis([2,2'-bipyridin]-5-ylethynyl)pyridine (L1) and bis(4-([2,2'-bipyridin]-5-ylethynyl)phenyl)methane (L2) were synthesized and used to generate two metallosupramolecular [Fe2(L)3](BF4)4 cylinders. The ligands and cylinders were characterized using elemental analysis, electrospray ionization mass spectrometry, UV-vis, 1H-, 13C and DOSY nuclear magnetic resonance (NMR) spectroscopies. The molecular structures of the [Fe2(L)3](BF4)4 cylinders were confirmed using X-ray crystallography. Both the [Fe2(L1)3](BF4)4 and [Fe2(L2)3](BF4)4 complexes crystallized as racemic (rac) mixtures of the ΔΔ (P) and ΛΛ (M) helicates. However, 1H NMR spectra showed that in solution the larger [Fe2(L2)3](BF4)4 was a mixture of the rac-ΔΔ/ΛΛ and meso-ΔΛ isomers. The host-guest chemistry of the helicates, which both feature a central cavity, was examined with several small drug molecules. However, none of the potential guests were found to bind within the helicates. In vitro cytotoxicity assays demonstrated that both helicates were active against four cancer cell lines. The smaller [Fe2(L1)3](BF4)4 system displayed low µM activity against the HCT116 (IC50 = 7.1 ± 0.5 µM) and NCI-H460 (IC50 = 4.9 ± 0.4 µM) cancer cells. While the antiproliferative effects against all the cell lines examined were less than the well-known anticancer drug cisplatin, their modes of action would be expected to be very different.

Synthetic Strategy Towards Heterodimetallic Half-Sandwich Complexes Based on a Symmetric Ditopic Ligand.

Multimetallic complexes have been shown in several examples to possess greater anticancer activity than their monometallic counterparts. The increased activity has been attributed to altered modes of action. We herein report the synthesis of a series of heterodimetallic compounds based on a ditopic ligand featuring 2-pyridylimine chelating motifs and organometallic half-sandwich moieties. The complexes were characterized by a combination of 1H NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis and single crystal X-ray diffraction. Investigations into the stability of representative complexes in DMSO-d 6 and 10% DMSO-d 6 /D2O revealed the occurrence of solvent-chlorido ligand exchange. Proliferation assays in four human cancer cell lines showed that the Os-Rh complex possessed minimal activity, while all other complexes were inactive.

Functionalization of metallabenzenes through nucleophilic aromatic substitution of hydrogen.

The cationic metallabenzenes [Ir(C(5)H(4){SMe-1})(κ(2)-S(2)CNEt(2))(PPh(3))(2)]PF(6) (1) and [Os(C(5)H(4){SMe-1})(CO)(2)(PPh(3))(2)][CF(3)SO(3)] (2) undergo regioselective nucleophilic aromatic substitution of hydrogen at the metallabenzene ring position γ to the metal in a two-step process that first involves treatment with appropriate nucleophiles and then oxidation. Thus, reaction between compound 1 and NaBH(4), MeLi, or NaOEt gives the corresponding neutral iridacyclohexa-1,4-diene complexes Ir(C(5)H(3){SMe-1}{H-3}{Nu-3})(κ(2)-S(2)CNEt(2))(PPh(3))(2) (Nu = H (3), Me (4), OEt (5)). Similarly, reaction between 2 and NaBH(4) or MeLi gives the corresponding osmacyclohexa-1,4-diene complexes Os(C(5)H(3){SMe-1}{H-3}{Nu-3})(CO)(2)(PPh(3))(2) (Nu = H (8), Me (9)). The metallacyclohexa-1,4-diene rings in all these compounds are rearomatized on treatment with the oxidizing agent O(2), CuCl(2), or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Accordingly, the cationic metallabenzene 1 or 2 is returned after reaction between 3 and DDQ/NEt(4)PF(6) or between 8 and DDQ/NaO(3)SCF(3), respectively. The substituted cationic iridabenzene [Ir(C(5)H(3){SMe-1}{Me-3})(κ(2)-S(2)CNEt(2))(PPh(3))(2)]PF(6) (6) or [Ir(C(5)H(4){SMe-1}{OEt-3})(κ(2)-S(2)CNEt(2))(PPh(3))(2)]PF(6) (7) is produced in a similar manner through reaction between 4 or 5, respectively, and DDQ/NEt(4)PF(6), and the substituted cationic osmabenzene [Os(C(5)H(3){SMe-1}{Me-3})(CO)(2)(PPh(3))(2)]Cl (10) is formed in good yield on treatment of 9 with CuCl(2). The starting cationic iridabenzene 1 is conveniently prepared by treatment of the neutral iridabenzene Ir(C(5)H(4){SMe-1})Cl(2)(PPh(3))(2) with NaS(2)CNEt(2) and NEt(4)PF(6), and the related starting cationic osmabenzene 2 is obtained by treatment of Os(C(5)H(4){S-1})(CO)(PPh(3))(2) with CF(3)SO(3)CH(3) and CO. The stepwise transformations of 1 into 6 or 7 as well as 2 into 10 provide the first examples in metallabenzene chemistry of regioselective nucleophilic aromatic substitutions of hydrogen by external nucleophiles. DFT calculations have been used to rationalize the preferred sites for nucleophilic attack at the metallabenzene rings of 1 and 2. The crystal structures of 1, 3, 6, and 7 have been obtained.

Carbonyl-chlorido(1-methyl-sulfanylpenta-1,3-dien-1-yl-5-yl-idene)bis-(triphenyl-phosphane)osmium(II).

The crystal structure of the title compound, [Os(C(6)H(7)S)Cl(C(18)H(15)P)(2)(CO)], confirms the formulation as an osmabenzene. There is a slightly distorted octa-hedral coordination environment at the Os(II) ion, with the triphenyl-phosphane ligands mutually trans and the chloride cis to the carbon bearing the -SMe substituent. Within the metallacyclic ring, the C-C distances are appropriate for aromatic bonds and the two Os-C distances are shorter than typical Os-C single bonds. The maximum deviation from the least-squares plane through the osmabenzene ring occurs for the carbon bearing the SMe substituent [0.1037 (18) Å].