Carbene Platinum Research Articles

Platinum‐Catalyzed Isomerization of Cyclopropenes to 1,3‐Dienes

AbstractHerein we report a platinum‐catalyzed isomerization of cyclopropenes to 1,3‐dienes. Diverse dienylated alcohols were obtained in 42–98 % yield. The synthetic potential of the products was demonstrated by their use in Diels–Alder cycloadditions with various dienophiles. Isotope labelling studies provide strong support for a mechanism involving pericyclic [1,5]‐σ‐bond rearrangement of a vinyl platinum carbene intermediate.

Triphenylphosphonium-functionalized N-heterocyclic carbene platinum complexes [(NHC-TPP+)Pt] induce cell death of human glioblastoma cancer stem cells

A growing body of experimental and clinical evidence suggests that rare cell populations, known as cancer stem cells (CSCs), play an important role in the development and therapeutic resistance of several cancers, including glioblastoma. Elimination of these cells is therefore of paramount importance. Interestingly, recent results have shown that the use of drugs that specifically disrupt mitochondria or induce mitochondria-dependent apoptosis can efficiently kill cancer stem cells. In this context, a novel series of platinum(II) complexes bearing N-heterocyclic carbene (NHC) of the type [(NHC)PtI2(L)] modified with the mitochondria targeting group triphenylphosphonium were synthesized. After a complete characterization of the platinum complexes, the cytotoxicity against two different cancer cell lines, including a cancer stem cell line, was investigated. The best compound reduced the cell viability of both cell lines by 50% in the low μM range, with an approximately 300-fold higher anticancer activity on the CSC line compared to oxaliplatin. Finally, mechanistic studies showed that the triphenylphosphonium functionalized platinum complexes significantly altered mitochondrial function and also induced atypical cell death.

Phosphorescent Cyclometalated Platinum(ii) Hexahydroimidazo[1,5‐a]pyridinylidene Complexes

AbstractThe synthesis of N‐heterocyclic carbene precursors based on the hexahydroimidazo[1,5‐a]pyridine and their corresponding cyclometalated platinum(II) carbene complexes is reported. All compounds are fully characterized by standard techniques and additionally X‐ray structures could be obtained for three complexes. The photophysical properties of these platinum complexes were investigated by absorption and photoluminescence measurements. All complexes showed strong phosphorescence at room temperature in the sky‐blue area with quantum yields of up to 71 %. Additionally, their electrochemical properties were examined by voltammetry experiments. All results were rationalized by quantum chemical DFT calculations (PBE0/6‐311G*).

Addition of aliphatic, secondary amines to coordinated isonitriles. N-acyclic carbene (NAC) platinum(II) complexes from trans-[Pt(μ-Cl)Cl(PPh3)

Isocyanide ligands RNC (R = 4-(MeO)C6H4-, PhCH2) react smoothly with trans-[Pt(μ-Cl)Cl(PPh3)]2 to afford trans-[PtCl2(PPh3)(CNR)] complexes, which are promptly converted, in solution, to the corresponding cis isomers. The obtained derivatives react with N,N-dialkylamines to afford the corresponding N-acyclic carbene (NAC) addition products. When alicyclic N,N-dialkylamine (Ŕ2NH, Ŕ= ethyl, benzyl) were used, only the expected neutral dichlorocarbene product cis-[PtCl2(PPh3)(Ŕ2NCN(H)R)] were obtained in high yields, while when cyclic amines R′2N^H were used (morpholine, piperidine, pyrrolidine), variable amounts of ionic [PtCl(PPh3)(R′2N^H)(R′2N^ CN(H)R)]Cl were observed, arising from the substitution of a residual chlorido ligand by the used amine. The amount of the ionic derivative observed depends on the amine nucleophilicity.

Observation of unsaturated platinum carbenes Pt2C2n - (n = 1-3) clusters: A photoelectron imaging spectroscopic and theoretical study.

The structural and bonding properties of the Pt2C2n - (n = 1-3) complexes have been investigated by mass-selected photoelectron velocity-map imaging spectroscopy with quantum chemical calculations. The adiabatic detachment energies and vertical detachment energies of Pt2C2n - have been obtained from the measured photoelectron imaging spectra. Theoretical results indicate that the lowest-energy isomers of Pt2C2n - (n = 1-3) possess linear chain-shaped configurations. The binding motif in the most stable isomer of Pt2C2 - has a linear cumulenic structure with a Pt=C=C=Pt configuration, and the structural characteristic persists up to all the lowest-energy isomers of the Pt2C4 - and Pt2C6 - anions. The chemical bonding analyses indicate that the Pt2C2n - (n = 1-3) complexes have multicenter two-electron characteristics.

Dichotomy of platinum(II) and gold(III) carbene intermediates switching from N- to O-selectivity

Pt(II) and Au(III)-mediated intermolecular divergent annulations of benzofurazans and ynamides highlighted the N- to O-selectivity of tunable metal carbene intermediates. PtCl2 with a bulky phosphite ligand resulted in the specific synthesis of six-membered quinoxaline N-oxides and successfully suppressed the in-situ deoxygenation of N-oxides. On the other hand, an unique gold(III) catalyst (2,6-di-MeO-PyrAuCl3) led to the five-membered ring products, benzimidazoles. A broad scope of functional groups was well compatible, delivering better yields and selectivities in contrast to conventional gold(I) catalysts. The different behavior of presumed platinum(II) and gold(III) carbenes with respect to chemoselectivity was intensively examined by experiments and DFT calculations. A detailed mechanistic study, based on DFT calculations, revealed that the highly electrophilic carbocation-like gold(III) carbene triggers an oxophilic cyclization, followed by a cascade ring contraction and acyl migration. On the contrary, the Pt carbene species is less cationic, favoring the formation of the six-membered ring via N-attack.

Fluorination Reactions at a Platinum Carbene Complex: Reaction Routes to SF3 , S(=O)F and Fluorido Complexes.

The electron‐rich Pt complex [Pt(IMes)2] (IMes: [1,3‐bis(2,4,6‐trimethylphenyl)‐2‐imidazolinylidine]) can be used as precursor for the syntheses of a variety of fluorido ligand containing compounds. The sulfur fluoride SF4 undergoes a rapid oxidative addition at Pt0 to yield trans‐[Pt(F)(SF3)(IMes)2]. A photolytic reaction of SF6 at [Pt(IMes)2] in the presence of IMes gave the fluorido complexes trans‐[Pt(F)2(IMes)2] and trans‐[Pt(F)(SF3)(IMes)2] along with trans‐[Pt(F)(SOF)(IMes)2] and trans‐[Pt(F)(IMes’)(IMes)] (IMes’: cyclometalated IMes ligand), the latter being products produced by reaction with adventitious water. trans‐[Pt(F)(SOF)(IMes)2] and trans‐[Pt(F)2(IMes)2] were synthesized independently by treatment of [Pt(IMes)2] with SOF2 or XeF2. A reaction of [Pt(IMes)2] with a HF source gave trans‐[Pt(H)(F)(IMes)2], and an intermediate bifluorido complex trans‐[Pt(H)(FHF)(IMes)2] was identified. Compound trans‐[Pt(H)(F)(IMes)2] converts in the presence of CsF into trans‐[Pt(F)(IMes’)(IMes)].

Chelating Phosphine-N-Heterocyclic Carbene Platinum Complexes via Catalytic Asymmetric Hydrophosphination and Their Cytotoxicity Toward MKN74 and MCF7 Cancer Cell Lines.

A series of activated vinyl azoles was hydrophosphinated in the presence of a chiral palladacycle catalyst under mild conditions to give enantioenriched phosphine azoles with moderate enantioselectivities and yields. The racemic phosphine azoles were transformed into eleven novel chelating phosphine-N-heterocyclic carbene (NHC) platinum complexes. The drug efficacies of nine selected phosphine-NHC platinum(II) chlorides in two cancer cell lines (MKN74 and MCF7) were evaluated, and two were found to exhibit activities comparable to that of cisplatin.

Platinum(II) Di-ω-alkenyl Complexes as "Slow-Release" Precatalysts for Heat-Triggered Olefin Hydrosilylation.

We describe the synthesis, characterization, and catalytic hydrosilylation activity of platinum(II) di-ω-alkenyl compounds of stoichiometry PtR2, where R = CH2SiMe2(vinyl) (1) or CH2SiMe2(allyl) (2), and their adducts with 1,5-cyclooctadiene (COD), dibenzo[a,e]cyclooctatetraene (DBCOT), and norbornadiene (NBD), which can be considered as slow-release sources of the reactive compounds 1 and 2. At loadings of 0.5 × 10-6-5 × 10-6 mol %, 1-COD is an active hydrosilylation catalyst that exhibits heat-triggered latency: no hydrosilylation activity occurs toward many olefin substrates even after several hours at 20 °C, but turnover numbers as high as 200000 are seen after 4 h at 50 °C, with excellent selectivity for formation of the anti-Markovnikov product. Activation of the PtII precatalyst occurs via three steps: slow dissociation of COD from 1-COD to form 1, rapid reaction of 1 with silane, and elimination of both ω-alkenyl ligands to form Pt0 species. The latent catalytic behavior, the high turnover number, and the high anti-Markovnikov selectivity are a result of the slow release of 1 from 1-COD at room temperature, so that the concentration of Pt0 during the initial stages of the catalysis is negligible. As a result, formation of colloidal Pt, which is known to cause side reactions, is minimized, and the amounts of side products are very small and comparable to those seen for platinum(0) carbene catalysts. The latent reaction kinetics and high turnover numbers seen for 1-COD after thermal triggering make this compound a potentially useful precatalyst for injection molding or solvent-free hydrosilylation applications.

Concentration Effect in Surface Plasmon-Coupled Phosphorescence (SPCP) Emission Engineering with Augmented S-Polarization from N-Heterocyclic Carbene Platinum(II) Complexes

Concentration Effect in Surface Plasmon-Coupled Phosphorescence (SPCP) Emission Engineering with Augmented S-Polarization from N-Heterocyclic Carbene Platinum(II) Complexes

N‐Heterocyclic Carbene Platinum Complexes: A Big Step Forward for Effective Antitumor Compounds

AbstractInvited for the cover of this issue is Stéphane Bellemin‐Laponnaz from the University of Strasbourg and CNRS, France. The cover image shows the formulas of various platinum(II) complexes with an N‐heterocyclic carbene ligand and a neutral ligand with two halides in the trans‐position. These complexes have a potent anticancer activity.

N‐Heterocyclic Carbene Platinum Complexes: A Big Step Forward for Effective Antitumor Compounds

The discovery of cisplatin is an important milestone in the history of successful anticancer drugs. This is also a notable example of the translational scientific achievement that remains a driving force in multidisciplinary research. The clinical success of cisplatin has led chemists to vary the ligands around the platinum metal to improve cisplatin's effectiveness while reducing its side effects. While there have been more failures than successes, key developments in the elucidation of mechanisms of the tumor‐resistance properties have been accomplished. N‐Heterocyclic carbene as ligand for organometallic chemistry is a relatively young area that offers new opportunities in many fields including bio‐inorganic chemistry. These ligands fit the prerequisites for metal drug development and recent achievements have demonstrated the great potential of these compounds. The properties of these metal NHC complexes also allow for easy post‐functionalization, thus enabling molecular diversity for efficient drug design. Overall, N‐heterocyclic carbene ligands reveal new opportunities for Pt drug development.

Synthesis and structural characterization of benzyl-functionalized N-heterocyclic carbene platinum complexes: Dramatic substituent effect on anti-cancer activity

A series of platinum (II) complexes bearing N-heterocyclic carbene NHC ligands functionalized by various benzyl moieties were synthesized and characterized. The molecular structure of two complexes has been confirmed by X-ray diffraction studies on single crystals. Investigation of in vitro cytotoxic activities against various cancer cell lines revealed a strong substituent effect: IC50 as low as 0.005 μM were obtained depending on the substituent on the benzyl moiety.

Square Planar Nucleophilic and Radical Pt(II) Carbenes

A square planar platinum(II) carbene complex [{PC(sp2)P}HPt(PMe3)] ([PC(sp2)P]H = (bis[2-(di-iso-propylphosphino)phenyl]methylene) was synthesized through the dehydrohalogenation of [{PC(sp3)HP}HPtCl] in a microwave reactor. The tert-butyl substituted analogue, [{PC(sp2)P}tBuPt(PMe3)] ([PC(sp2)P]tBu = bis[2-(di-iso-propylphosphino)-4-tert-butylphenyl]methylene), was synthesized via an analogous route. The nucleophilic nature of the carbene carbon was confirmed through DFT calculations and reactivity with HCl. Additionally, [{PC(sp2)P}HPt(PMe3)] was treated with 0.5 equiv of I2 to generate a paramagnetic product, [{PC(sp2)P}HPtI]. The Evans method and EPR spectroscopy revealed that a one-electron oxidation occurred at the carbene carbon, thus generating a persistent radical carbene.

A highly efficient and selective antitumor agent based on a glucoconjugated carbene platinum(ii) complex

New five-coordinate Pt(ii) complexes containing a glycosylated carbene fragment were synthesized. A member of this class shows very high in vitro cytotoxicity and an exceptional selectivity toward malignant cells. The complex lacking the sugary portion fails in the recognition of cancer cells. The results support the use of glycosylation in the design of carbene Pt-based anticancer agents.

N-Heterocyclic Carbene-Polyethyleneimine (PEI) Platinum Complexes Inducing Human Cancer Cell Death: Polymer Carrier Impact.

The high interest in N-Heterocyclic platinum carbene complexes in cancer research stems from their high cytotoxicity to human cancer cells, their stability, as well as their ease of functionalization. However, the development of these new molecules as anticancer agents still faces multiple challenges, in particular solubility in aqueous media. Here, we synthesized platinum-NHC bioconjugates that combine water-solubility and cytotoxicity by using polyethyleneimine as polymer carrier. We showed on 8 different types of cells that the activity of these conjugates is modulated by the size of the polymer and the overall density of metal ions onto polymer chains. Using HCT116 cells, the conjugates displayed an effective activity after only 45 min of exposure in vitro correlated with a quick uptake by the cells as shown by the use of various fluorescent-tagged derivatives.

Synthesis, characterization, and photophysical properties of cyclometalated N-Heterocyclic carbene Platinum(II) complexes

Thiophene and benzothiophene ligands containing N-heterocyclic carbene (NHC) moieties were used to synthesize five and six-membered Pt(II) metallacycles. Ligand scaffolding was synthesized using two methods. The ligands were synthesized using a coupling reaction, utilizing Cu2O as the catalyst or were synthesized using a nucleophilic substitution reaction. The ligands were then metalated by chelate-assisted CH activation. The synthesis, characterization, reactivity, and photophysical properties of these NHC-functionalized, cyclometalated products are reported.

Highly Stable and Strongly Emitting N-Heterocyclic Carbene Platinum(II) Biaryl Complexes.

C^C cyclometalated platinum(II) triplet emitters bearing electronically different N-heterocyclic carbenes-(1,3-diisopropyl-4-(trifluoromethyl)-imidazol-2-ylidene (d), 1,3-diisopropyl-benzimidazol-2-ylidene (e), and 1,3-diisopropyl-imidazol-2-ylidene (f))-as neutral ligands and biphenyl (bph) as well as its fluorinated derivative octafluorobiphenyl (oFbph) as dianionic cyclometalating ancillary ligand were synthesized and structurally characterized by 1H, 13C, 19F, and 195Pt NMR, single crystal X-ray diffraction, and HR-ESI-MS studies. Detailed photophysical investigations carried out reveal a strong influence on the excited-state properties exerted by the electronic nature of the N-heterocyclic carbenes as well as the fluorine functional groups on the ancillary biphenyl moiety. The solid-state structures of all complexes reveal a nearly planar and slightly distorted square planar geometry around the platinum center. Introduction of fluorine groups into the ligand framework leads to a less structured emission centered at 513 nm in poly(methyl methacrylate) (PMMA) thin films, compared to the highly structured emission profile of the bph analogues. Additionally, a hypsochromic shift of approximately 10-12 nm was found in the absorption as well as in the emission profiles and is attributed to the electron deficient nature of the oFbph ligand. Three wt % of the compounds doped in PMMA exhibit photoluminescence efficiencies as high as 92% in thin films. DFT and TD-DFT calculations on selected molecules revealed the charge transfer to be an admixture of intraligand (3ILCT) and metal-to-ligand charge transfer (3MLCT) and the frontier orbitals corresponding to the emission to be mainly localized on the bph and oFbph ligands, which is consistent with the observations from the photophysical investigations. The thermal stability of the complexes evaluated by thermogravimetric analysis (TGA) shows an enhanced thermal stability for the complexes bearing fluorine functional groups.

Synthesis of a Novel Type of 2,3'-BIMs via Platinum-Catalysed Reaction of Indolylallenes with Indoles.

Optimisation, scope and mechanism of the platinum‐catalysed addition of indoles to indolylallenes is reported here to give 2,3′‐BIMs with a novel core structure very relevant for pharmaceutical industry. The reaction is modulated by the electronic properties of the substituents on both indoles, with the 2,3′‐BIMs favoured when electron donating groups are present. Although simple at first, a complex mechanism has been uncovered that explains the different behaviour of these systems with platinum when compared with other metals (e.g. gold). Detailed labelling studies have shown Pt‐catalysed 6‐endo‐trig cyclisation of the indollylallene as the first step of the reaction and the involvement of two cyclic vinyl‐platinum intermediates in equilibrium through a platinum carbene, as the key intermediates of the catalytic cycle towards the second nucleophilic attack and formation of the BIMs.

In Search of Deeper Blues: Trans-N-Heterocyclic Carbene Platinum Phenylacetylide as a Dopant for Phosphorescent OLEDs.

A trans-N-heterocyclic carbene (NHC) platinum(II) acetylide complex bearing phenyl acetylene ligands (NPtPE1) has been synthesized via the Hagihara reaction in 64% yield. The complex features spectrally narrow deep blue emission with a phosphorescence quantum yield (0.30) and lifetime (∼10 μs) in the solid state. The modest quantum yield and lifetime make NPtPE1 a candidate for incorporation into an organic light emitting diode (OLED). Prototype devices exhibited a maximum EQE of 8% with CIE (0.20,0.20). To the best of our knowledge, this is the first example of a platinum(II) acetylide bearing NHC ligands to be incorporated into an OLED.