LNL-Carbazole Pincer Ligand: More than the Sum of Its Parts.

The utility of carbazole in photo-, electro-, and medicinal applications has ensured its widespread use also as the backbone in tridentate pincer ligands. In this review, the aim is to identify and illustrate the key features of the LNL-carbazolide binding to transition metal centers (with L = flanking donor moieties, e.g., C, N, P, and O-groups) in a systematic bottom-up progression to illustrate the marked benefits attainable from (i) the rigid aromatic carbazole scaffold (modulable in both the 1,8- and 3,6-positions), (ii) the significant electronic effect of central carbazole-amido binding to a metal, and the tunable sterics and electronics of both the (iii) flanking donor L-moieties and (iv) the wingtip R-groups on the L-donors, with their corresponding influence on metal coordination geometry, d-electron configuration, and resultant reactivity. Systematic implementation of the ligand design strategies not in isolation, but in a combinatorial approach, is showcased to demonstrate the potential for functional molecules that are not only modulable but also adaptable for wide-ranging applications (e.g., stereoselective (photo)catalysis, challenging small molecule activation, SET and redox applications, and even applications in chemotherapeutics) as an indication of future research efforts anticipated to stem from this versatile pincer assembly, not only for the transition metals but also for s-, p-, and f-block elements.

Cancer molecular biology and strategies for the design of cytotoxic gold(I) and gold(III) complexes: a tutorial review.

This tutorial review highlights key principles underpinning the design of selected metallodrugs to target specific biological macromolecules (DNA and proteins). The review commences with a descriptive overview of the eukaryotic cell cycle and the molecular biology of cancer, particularly apoptosis, which is provided as a necessary foundation for the discovery, design, and targeting of metal-based anticancer agents. Drugs which target DNA have been highlighted and clinically approved metallodrugs discussed. A brief history of the development of mainly gold-based metallodrugs is presented prior to addressing ligand systems for stabilizing and adding functionality to bio-active gold(I) and gold(III) complexes, particularly in the burgeoning field of anticancer metallodrugs. Concepts such as multi-modal and selective cytotoxic agents are covered where necessary for selected compounds. The emerging role of carbenes as the ligand system of choice to achieve these goals for gold-based metallodrug candidates is highlighted prior to closing the review with comments on some future directions that this research field might follow. The latter section ultimately emphasizes the importance of understanding the fate of metal complexes in cells to garner key mechanistic insights.

A Cytotoxic Bis(1,2,3-triazol-5-ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation.

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) AuI -CNC pincer complex suitable for oxidation to the redox-stable [AuIII (CNC)Cl]+ cation. Although the ligand salt and the [AuIII (CNC)Cl]+ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [AuIII (CNC)Cl]+ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII (CNC)Cl]+ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic π-type interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.

Chelated Fischer carbene complexes of annulated thiophenes: synthesis, structure and electrochemistry.

Two (thieno[3,2-b]thiophene) and three annulated thiophenes (dithieno[2,3-b;3',2'-d]thiophene and dithieno[3,2-b;2',3'-d]thiophene) were employed as building blocks to synthesize linear or semi-circular chelated mononuclear biscarbene and dinuclear tetracarbene complexes. The electronic properties of the annulated thienylene chelated carbene complexes were investigated by cyclic voltammetry experiments and compared to non-chelated Fischer-type monocarbene complexes. Density functional theory (DFT) calculations were used to assign the redox events and to probe the extent of electron delocalisation as well as the possibility of electronic (intramolecular metal-metal) communication as a result of intervalence. The differences of these electronic properties in the conjugated chelated carbene complexes are compared to chelated carbene compounds without a linear conjugated pathway.

Fischer Carbene Complexes of Iridium(I) for Application in Catalytic Transfer Hydrogenation.

New examples of the very rare class of iridium(I) Fischer carbene complexes (FCCs) are reported from the facile transmetalation from group 6 FCCs. Postcomplexation modification of either the carbene ligand or the ancillary coligands results in a tunable IrI metal center, for unprecedented application as a (pre)catalyst in a benchmark transfer hydrogenation reaction. The introduction of an aminocarbene ligand with a pendant N-donor moiety capable of hemilabile coordination yielded the best catalytic results with turnover frequencies reaching 445 h-1 and requiring 0.1 mol % catalyst and 0.5 mol % base loading, respectively.

Synthesis and Photophysical Properties of T-Shaped Coinage-Metal Complexes.

The photophysical properties of a series of T-shaped coinage d10 metal complexes, supported by a bis(mesoionic carbene)carbazolide (CNC) pincer ligand, are explored. The series includes a rare new example of a tridentate T-shaped AgI complex. Post-complexation modification of the AuI complex provides access to a linear cationic AuI complex following ligand alkylation, or the first example of a cationic square planar AuIII -F complex from electrophilic attack on the metal centre. Emissions ranging from blue (CuI ) to orange (AgI ) are obtained, with variable contributions of thermally-dependent fluorescence and phosphorescence to the observed photoluminescence. Green emissions are observed for all three gold complexes (neutral T-shaped AuI , cationic linear AuI and square planar cationic AuIII ). The higher quantum yield and longer decay lifetime of the linear gold(I) complex are indicative of increased phosphorescence contribution.

Synthesis of heterobimetallic gold(i) ferrocenyl-substituted 1,2,3-triazol-5-ylidene complexes as potential anticancer agents.

1,2,3-Triazol-5-ylidene (trz) complexes of gold(i) containing a ferrocenyl substituent on the C4-position of the trz ring were synthesized to yield the neutral heterobimetallic gold(i) trz chlorido (2), gold(i) trz phenyl (3), and the cationic gold(i) trz triphenylphospine (5) complexes. In order to compare the effect of silver(i) as central metal vs. gold(i), [Ag(trz)2]+ (4) was also prepared, while variation of the C4-1,2,3-triazol-5-ylidene substituent from a ferrocenyl to a phenyl group was done to prepare the monometallic analogue of 5, namely the cationic Au(i) trz triphenylphosphine complex 6. The complexes were characterised with spectroscopic and electrochemical methods, and the single crystal X-ray structures of 2-6 were determined. NMR stability studies of 5 as a representative example of the series of complexes were performed to confirm the stability of the complexes in the solvent dimethylsulfoxide and in aqueous solution. The anti-cancer potential of 5 was evaluated against the lung cancer cell lines A549 and H1975, and the human embryonic kidney cell line (HEK-293) was used as a non-cancer model. IC50 values of 0.89, 0.23 and 5.43 µM, respectively, were obtained for A549, H1975 and HEK-293, respectively, indicating the activity and selectivity of 5 for cancer cells. Fluorescence microscopy experiments as a preliminary mode-of-action study evidenced an apoptotic cell death mechanism rather than necrotic cell death.

Mono-, di- and tetrarhenium Fischer carbene complexes with thienothiophene substituents.

The oxidative cleaving of a rhenium-rhenium bond by bromine in binuclear Fischer carbene complexes proves to be an effective method to prepare mononuclear bromido-carbene complexes. The reaction of mono- and dilithiated thieno[2,3-b]thiophene (2,3-b-TTH2) and thieno[3,2-b]thiophene (3,2-b-TTH2) with [Re2(CO)10] affords dirhenium nonacarbonyl ethoxycarbene complexes, [Re2(CO)9{C(OEt)2,3-b-TTH}] (1a) and [Re2(CO)9{C(OEt)3,2-b-TTH}] (1b), and the tetrarhenium bis(ethoxycarbene) complexes from the dilithiated thiophene substrates, [Re2(CO)9-µ-{C(OEt)-2,3-b-TT-C(OEt)}Re2(CO)9] (2a) and [Re2(CO)9-µ-{C(OEt)-3,2-b-TT-C(OEt)}Re2(CO)9] (2b) featuring bridging thiophene linkers. Rhenium-rhenium bond cleavage by bromine of the monocarbene complexes yielded the scarce class of monorhenium bromido-carbene complexes, cis-[Re(CO)4{C(OEt)2,3-b-TTH}Br] (3a) and cis-[Re(CO)4{C(OEt)3,2-b-TTH}Br] (3b), while the corresponding reaction of the biscarbene tetrarhenium carbonyl complex of thieno[2,3-b]thiophene afforded the cleaving of both metal-metal bonds to give the novel dirhenium biscarbene dibromido complex with a thienothiophene spacer, [Re(CO)4Br-µ-{C(OEt)-2,3-b-TT-C(OEt)}Re(CO)4Br] (4a). A new indirect aminolysis route is described to prepare the chlorido dimethylaminocarbene complex 5acis-[Re(CO)4{C(NMe2)2,3-b-TTH}Cl], with unexpected cleavage of the Re-Re bond. Single crystal X-ray diffraction studies were performed on 1a, 2a, 3a, 5a, 1b and 3b. Spectroscopic and electrochemical methods are employed to investigate the electronic effect of the different conjugation pathways in the different thienothiophenyl carbene substituents, and the replacement of the rhenium pentacarbonyl fragment with a bromido ligand.

A Hemilabile and Cooperative N-Donor-Functionalized 1,2,3-Triazol-5-Ylidene Ligand for Alkyne Hydrothiolation Reactions.

A series of novel cationic and neutral Rh complexes with an N-donor-functionalized 1,2,3-triazol-5-ylidene (TRZ) ligand (in which the pendant N donor is NHBoc, NH2 , or NMe2 ) is described. The catalytic activity of these complexes was evaluated in the hydrothiolation of alkynes. Among the catalysts, a neutral dicarbonyl complex featuring the tethered-NBoc amido-TRZ ligand proved very selective for alkyne hydrothiolation with an aryl thiol. Remarkably, the reaction could be carried out in the absence of pyridine or base additive. In addition, during the reaction, no evidence for oxidative addition of the thiol S-H bond was observed, strongly suggesting a reaction pathway in which a bifunctional ligand is involved. Experimental and theoretical mechanistic investigations suggest a ligand-assisted deprotonation of thiol, hemilabile dissociation of amine from the metal, and thiolate coordination, which is indicative of a different reaction mechanism to those previously reported for related alkyne hydrothiolation reactions.

Nucleophilic T-Shaped (LXL)Au(I)-Pincer Complexes: Protonation and Alkylation.

We report the synthesis and reactivity of unusual T-shaped (LXL)Au(I)-pincer complexes, based on a carbazole framework flanked by two mesoionic carbenes (MICs). In contrast to other Au(I) complexes, these complexes react with electrophiles. Protonation and alkylation occur either at the metal or the ligand, depending on steric factors. Of particular interest, protonation at gold leads to an unprecedented cationic Au(III) hydride, which gives a 1H NMR resonance at δ -8.34 ppm. The reactivity of this "hydride", however, shows protic and not hydridic behavior.

A rhodium(I)-oxygen adduct as a selective catalyst for one-pot sequential alkyne dimerization-hydrothiolation tandem reactions.

An air-stable rhodium(I)-oxygen adduct featuring a CNC-pincer ligand, based on 1,2,3-triazol-5-ylidenes, catalyzes the homo-dimerization and hydrothiolation of alkynes, affording the gem-enyne and α-vinyl sulfide isomers, respectively, with excellent selectivity. A one-pot stepwise strategy allows the selective catalytic preparation of non-symmetric bis-vinyl sulfides, as well as the alkyne dimerization-hydrothiolation tandem reactions.

Synthesis and properties of mono- and dimetal Fischer multicarbene complexes derived from thiophene and thieno[2,3-b]thiophene.

Access to multicarbene complexes of a fused thienothiophene substrate was obtained by the use of the tetrabrominated thieno[2,3-b]thiophene precursor in a lithium-bromide exchange reaction, followed by nucleophilic attack on metal hexacarbonyls (M = Cr, W). Subsequent alkylation afforded unique triscarbene complexes [M(CO)4{{C(OEt)}2C6H1S2C(OEt)}M(CO)5] (M = Cr 12, W 13) featuring three non-equivalent carbene ligands on a single thiophene linker, as well as the bischelated tetracarbene complexes [M(CO)4{{C(OEt)}2C6S2{C(OEt)}2}M(CO)4] (M = Cr 14, W 15). The triscarbene complexes 12 and 13 are the first examples of multi-alkoxycarbene complexes featuring three non-equivalent carbene ligands. The reaction also afforded the chelated mononuclear biscarbene complexes [M(CO)4{C(OEt)}2C6H2S2] (M = Cr 10, W 11) in low yields. Similarly, employing tetrabromothiophene as precursor yielded the mononuclear chelate biscarbene complexes [M(CO)4{C(OEt)}2C4H2S] (M = Cr 6, W 7) and the dinuclear tetracarbene complexes [M(CO)4{{C(OEt)}2C4S{C(OEt)}2}M(CO)4] (M = Cr 8, W 9). Modification of the classic Fischer carbene synthetic methodology to a process of stepwise additions of lithiating agent and metal carbonyls to thieno[2,3-b]thiophene, facilitates the formation of the mixed metal biscarbene complex [W(CO)5C(OEt){C6H2S2}C(OEt)Cr(CO)5] 5, as analogue of the homonuclear biscarbene complexes [M(CO)5C(OEt){C6H2S2}C(OEt)M(CO)5], (M = Cr 3, W 4). The monocarbene complexes [M(CO)5{C(OEt)C6H3S2}], (M = Cr 1, W 2) were also obtained in high yields, and the molecular structures of the tungsten complexes, with the exception of 9 and 11, were confirmed by single crystal X-ray diffraction studies.

Redox behaviour of cymantrene Fischer carbene complexes in designing organometallic multi-tags.

A series of Group 7 Fischer carbene complexes, [Cp(CO)2 Mn(I) =C(OEt)Ar] (Cp=cyclopentadienyl, Ar=Th=thienyl (1 a), Ar=Fu=furyl (2 a), Ar=Fc=ferrocenyl (3 a)) and biscarbene complexes, [Cp(CO)2 MnC(OEt)Ar'(OEt)CMn(CO)2 Cp] (Ar'=Th'=2,5-thienylene (1 b), Ar'=Fu'=2,5-furylene (2 b), Ar'=Fc'=1,1'-ferrocendiyl (3 b)) was synthesized and characterized. Chemical oxidation of [Cp(CO)2 MnC(OEt)Fc] (3 a) and isolation of the oxidised species [3 a][PF6 ] possessing a Mn(II) centre proved possible below -30 °C in dichloromethane solution. The ESR spectrum of the transiently stable radical cation, [3 a][PF6 ], confirmed the presence of a low-spin Mn(II) centre characterized by a rhombic g tensor (gx =1.975, gy =2.007 and gz =2.130) in frozen dichloromethane at 77 K with (55)  Mn hyperfine coupling constants A1 , A2 and A3 of 115, 33 and 43 G, respectively. Electrochemical studies demonstrated the influence of the Ar substituent on the oxidation potential. All complexes showed that the redox potentials of carbene double bond reduction and Mn(I) oxidation were dependent on the type of Ar group, but only 3 b showed resolved oxidations for the two Mn(I) centres. Surprisingly, Mn(I) oxidation occurs at lower potentials than ferrocenyl oxidation. Density functional theory (DFT) calculations were carried out to delineate the nature of the species involved in the oxidation and reduction processes and clearly confirm that oxidation of Mn(I) is favoured over that of ferrocene.

Isolation of a potassium bis(1,2,3-triazol-5-ylidene)carbazolide: a stabilizing pincer ligand for reactive late transition metal complexes.

The synthesis and X-ray crystal structure of a potassium adduct of a monoanionic CNC-pincer ligand featuring two mesoionic carbenes is reported. Owing to the peculiar electronic and steric properties of this ligand, the first neutral stable Ni(II)-hydride, and an unusual Cu(II) complex displaying a seesaw geometry, have been isolated.

Fischer-type gold(I) carbene complexes stabilized by aurophilic interactions.

The synthesis and structure of rare acyclic alkoxy- and aminocarbene complexes of gold(i) are reported, including a novel ferrocenophane dinuclear biscarbene complex. X-Ray diffraction analyses and DFT calculations reveal that these complexes are stabilized by genuine aurophilic interactions.

Metal-metal interaction in Fischer carbene complexes: a study of ferrocenyl and biferrocenyl tungsten alkylidene complexes.

A series of ferrocenyl (Fc = ferrocenyl; fc = ferrocen-1,1'-diyl) and biferrocenyl (Bfc = 1',1″-biferrocenyl; bfc = 1',1″-biferrocen-1,1‴-diyl) mono- and biscarbene tungsten(0) complexes of the type [(CO)5W═C(OMe)R] (1, R = Fc; 3, R = Bfc) and [(CO)5W═C(OMe)-R'-(OMe)C═W(CO)5] (2, R' = fc; 4, R' = bfc) were synthesized according to the classical synthetic methodology by reacting W(CO)6 with LiR (R = Fc, fc, bfc), followed by a subsequent alkylation using methyl trifluoromethanesulfonate. Electrochemical investigations were carried out on these complexes to get a closer insight into the electronic properties of 1-4. The ferrocenyl and biferrocenyl moieties in 1-4 show reversible one-electron redox events. It was further found that the Fischer carbene unit is reducible in an electrochemical one-electron transfer process. For the tungsten carbonyl moieties, irreversible oxidation processes were found. In addition, charge transfer studies were performed on 1-4 using in situ UV-vis-NIR and infrared spectroelectrochemical techniques. During the UV-vis-NIR investigations, typical low energy transitions for the mixed-valent biferrocenyl unit were found. A further observed high energy NIR absorption is attributed to a metal-metal charge transfer transition between the tungsten carbonyl fragment and the ferrocenyl/biferrocenyl group in the corresponding oxidized states, which can be described as class II systems according to Robin and Day. This assignment was verified by infrared spectroelectrochemical studies. The electrochemical investigations are supported by density functional theory calculations. The structural properties of 1-4 in the solid state were investigated by single-crystal X-ray diffraction studies showing no substituent effects on bond lengths and angles. The biferrocenyl derivatives exhibit syn-conformation of the ferrocenyl and carbene building blocks.

Substituent effects on the electrochemical, spectroscopic, and structural properties of Fischer mono- and biscarbene complexes of chromium(0).

A series of ten ferrocenyl, furyl, and thienyl mono- and biscarbene chromium(0) complexes were synthesized and characterized spectroscopically and electrochemically. The single crystal structure of the biscarbene complex [(CO)5Cr═C(OEt)-Fu'-(OEt)C═Cr(CO)5] (4a) was determined: C20H12Cr2O13; triclinic; P1; a = 6.2838(5), b = 12.6526(9), c = 29.1888(19) Å, α = 89.575(2), ß = 88.030(2), γ = 87.423(2)°; Z = 4. Results from an electrochemical study in CH2Cl2 were mutually consistent with a computational study in showing that the carbene double bond of 1-6 is reduced to an anion radical, (-)Cr-C• at formal reduction potentials < -1.7 V vs FcH/FcH(+). The Cr centers are oxidized in two successive one electron transfer steps to Cr(II) via the Cr(I) intermediate. Only Cr(I) oxidation is electrochemically irreversible. Dicationic Cr(II) species formed upon two consecutive one-electron oxidation processes are characterized by a peculiar bonding situation as they are stabilized by genuine CH···Cr agostic interactions. With respect to aryl substituents, carbene redox processes occurred at the lowest potentials for ferrocene derivatives followed by furan complexes. Redox process in the thiophene derivatives occurred at the highest potentials. This result is mutually consistent with a (13)C NMR study that showed the Cr═C functionality of furyl complexes were more shielded than thienyl complexes. The NHBu carbene substituent resulted in carbene complexes showing redox processes at substantially lower redox potentials than carbenes having OEt substituents.

Electrochemical illumination of thienyl and ferrocenyl chromium(0) Fischer carbene complexes.

A series of ferrocenyl and thienyl mono- and biscarbene chromium(0) complexes 1-6 were synthesised. The complexes were characterised both spectroscopically and electrochemically, and the single crystal X-ray structure of 3 was determined. Electrochemical measurements in CH2Cl2 revealed that the carbene double bond of 1-6 is reduced to an anion radical, (-)Cr-C˙ at formal reduction potentials <-1.7 V vs. FcH/FcH(+). A computational study on 1, 3 and 4 (B3LYP/def2-SVP level) is consistent with electrochemical results in showing that electrochemically generated chromium(I) species may be further electrochemically irreversibly oxidised to chromium(II) at Epa > 0.95 V. The reactivity towards follow-up chemical reactions of the anodically produced Cr(II) species is much higher than the reactivity of the cathodically produced radical anions as the latter was still observably reoxidised to the parent Cr=C species at fast scan rates. The ferrocenyl group is oxidised electrochemically reversibly to ferrocenium at larger potentials than the electrochemically reversible oxidation of the Cr(0) centre to Cr(I). That all redox centres in 1-6 are involved in one-electron transfer steps was confirmed by comparing the ferrocenyl voltammetric wave with those of the other redox centres in linear sweep voltammetric experiments. The ferrocenyl group was electrochemically shown to stabilise the Cr=C centre almost as much as the NHBu, and much more than the ethoxy and thienyl groups.

{µ-5-[1,3-Bis(2,4,6-trimethyl-phen-yl)-3H-imidazolium-2-yl]-2-(2-oxoethenyl-1κC)furan-3-yl-2κC}-µ-hydrido-bis(tetra-carbonyl-rhenium) tetra-hydro-furan 0.67-solvate.

The title complex, [Re(2)(C(27)H(25)N(2)O(2))H(CO)(8)]·0.67C(4)H(8)O, was formed as a product in the reaction of a rhenium(I)-Fischer carbene complex with a free NHC carbene. The coordination environment about the two Re atoms is slightly distorted octahedral, including a bridging H atom. The imidazolium and furan groups are almost coplanar, whereas the mesityl substituents show an almost perpendicular arrangement with respect to both heterocyclic units. Mol-ecules of the complex pack in such a way as to form channels parallel with the bc unit-cell face diagonal running through the unit face diagonal. These channels are partially occupied by tetra-hydro-furan solvent mol-ecules.

1,3-Bis(2,4,6-trimethyl-phen-yl)-3H-imidazol-1-ium tetra-oxidorhenate(VII).

The title compound, (C(21)H(25)N(2))[ReO(4)], was formed as the unexpected product in an attempted synthesis of a rhenium(I)-N-heterocyclic carbene (NHC) complex. The compound has crystallographic mirror symmetry with both the cation and the tetrahedral anion located across a mirror plane. The cation and anion are linked by a C-H⋯O hydrogen bond.