Cyclopalladated Complexes Research Articles

Dynamic amine sorting enables multiselective construction of unsymmetrical chiral diamines.

Precisely differentiating chemicals featuring minor discrepancies is the prerequisite for achieving high selectivities in both chemical synthesis and biological activities. However, efficient strategies to differentiate and sort such congeneric compounds are lacking, posing daunting challenges for synthetic endeavours aimed at their orderly incorporation. Here we report a dynamic amine-sorting strategy that incorporates the chemoselective formation of the aminomethyl cyclopalladated complex to achieve the efficient differentiation of amine congeners. A series of amines sharing similar three-dimensional structures and properties, as well as possessing notoriously strong binding ability to metals, can be efficiently differentiated, enabling the highly chemo-, regio- and enantioselective multicomponent aminomethylamination of dienes to construct a variety of unsymmetrical chiral diamines. This dynamic amine-sorting strategy tackles the long-standing challenge of precise differentiation and orderly incorporation of aliphatic amines with subtle differences. From a broader perspective, the success demonstrates that meticulously designed metal complexes can provide flexible and general solutions for controlling delicate selectivities in sophisticated synthesis.

Synthesis of tetranuclear cyclopalladated complex using thiosemicarbazone derivative ligand: Spectral, biological and molecular docking studies

New tetranuclear Palladium(II) complex, (Pd-(OMe)-TSC)4, has been successfully synthesized from the reaction of potassium tetrachloridopalladate (II) salt (K2[PdCl4]) with methoxy‑functionalized thiosemicarbazone ligand, OMe-TSC, and characterized using various spectroscopic techniques such as FT-IR, UV–Vis, 1H NMR, 13C NMR, 1H-1H COSY, 13C-APT, 1H-13C HMQC, elemental analyses and high-resolution mass spectroscopy. The in-vitro anticancer activity was investigated by using MTT test in breast cancer cells (MCF-7 cell line). Anticancer activity of the complex was higher than ligand and the results inferred that the complex showed comparable activitiy with cis-platin. Furthermore, fluorescence and UV–Vis spectroscopies had been used to investigate the binding interaction of the synthesized samples with Bovine Serum Albumin (BSA). Three different drugs namely, Warfarin, Ibuprofen, and Digoxin, were employed to study the competitive bindings to different sites on BSA. The obtained results demonstrated that the binding sites were mainly located within site I and II of BSA for the (Pd-(OMe)-TSC)4 complex and (OMe)-TSC ligand, respectively. In addition, the suggested structures of ligand and complex have been optimized by semi-emprical method and the aforementioned results of BSA interaction were supported by molecular docking and molecular dynamics calculations. Also, The free binding energies of -4.16 kcal/mol and -5.80 kcal/mol were calculated for the interaction of the ligand and complex with SARS-CoV-2, respectively, which indicated the interaction is a spontaneous process and is a evidence for antiviral potential of (Pd-(OMe)-TSC)4 complex.

Enantioselective Ring-Closing Aminomethylamination of Allylic Aminodienes with Aminals Triggered by C-N Bond Metathesis.

A conceptually novel strategy utilizing a cyclopalladated complex as an electrophile to activate the C-N bond for the C-N bond metathesis between allylamines and aminals is developed, which enables an efficient ring-closing aminomethylamination of allylic aminodienes and aminals. The reaction proceeds under mild reaction conditions and displays a remarkable scope. Utilizing a modified Trost-type diphosphine as the ligand, this method enables the efficient synthesis of 5-10-membered aminoallylated chiral N-heterocycles in good yields with high enantiomeric excess values.

Palladium-catalyzed ring-closing reaction of enynols with aminals via methylene transfer and C–N bond activation

The aminomethyl cyclopalladated complex is identified as a key intermediate for promoting the C–N bond activation of tertiary amines via reductive elimination and oxidative addition sequence. This strategy has enabled a palladium-catalyzed ring-closing reaction of enynols with aminals via methylene transfer and C–N bond activation, which provides rapid access to densely functionalized O-heterocycle containing allenic amines. The dual roles of the cyclopalladated complex, first as an aminomethylene-carrying reagent and then as a catalyst for C–N bond activation, have enabled a rare cascade redox-neutral methylene transfer and cyclization process that can simultaneously construct O-heterocycle framework and allenic amine functionality.

Versatile halogenation via a CNHC^Csp3 palladacycle intermediate.

Stable cyclopalladated complexes containing an (sp3)C-Pd bond were synthesized via α-CH2 deprotonation and palladation of N-alkyl groups of carbene ligands bearing electron-withdrawing substituents. The strong electron donating strengths of the resulting CNHC^Csp3 chelators were experimentally identified, and the palladacycle underwent template-directed, versatile C-halogenation with X2.

Rational design of fluorescent chemosensor for Pd2+ based on the formation of cyclopalladated complex

According to the assumption that the formation of C–Pd bond becomes a cyclopalladated complex (CPC), we designed and synthesized two C–N–N pincer ligands of BODIPY appended 2,2′-bipyridine derivatives (BP and BPB). It has been confirmed that the C–Pd bond does exist and plays a crucial role in “on-off” fluorescence behavior. Based on it, a coordination-induced fluorescence quenching sensor for Pd2+ was constructed. The results indicated that BP possessed high sensitivity and specificity for Pd2+ in solution. The limit of detection (LOD) of BP is determined to be 0.97 nM within a linear range between 1.0 and 50.0 nM, meanwhile, the platinum-group ions demonstrate no interference. The bio-imaging application of BP was investigated and it exhibited a promising vitro test for fluorescent imaging of Pd2+ ions in MCF-7 cells. Meanwhile, BPB coated sensor label for Pd2+ was set up. The visible color variation was displayed under UV light with increasing concentrations of Pd2+. Briefly speaking, fluorescence probes of BP and BPB offer new approaches for Pd2+ detection in a lab and on-site test, as well as the vivo imaging. Then, with the aid of (TD)DFT calculation, the internal reason for the optical difference between the two ligands was disclosed. This concept of CPC containing a Pd–C covalent bond provides a promising perspective of coordination fluorescence sensors.

Reactions of cyclopalladated complexes with boronic acids

Six known C(sp2),N and C(sp3),N cyclopalladated complexes derived from N,N-dimethylbenzylamine, 4,4-dimethyl-2-phenyl-2-oxazoline, 2-tert-butyl-2,2-dimethyl-2-oxazoline, O-methyloxime of d-camphor, 8-methylquinoline, and N,N-dimethylhydrazone of d-camphor were synthesized and used in CC bond formation reactions with aryl, benzyl and allylboronic acids or esters. Two protocols for a successful CC coupling were developed; both involve the use of a base and the conversion of dimeric cyclopalladated complexes to the mononuclear derivatives with PPh3 as an auxiliary ligand. The C(sp2)–C(sp2) bond formation was achieved by reacting mononuclear complexes of N,N-dimethylbenzylamine and 4,4-dimethyl-2-phenyl-2-oxazoline with ArB(OH)2 in acetone at 60 °C in the presence of Cs2CO3. Reactions of (i) C(sp3),N complexes PPh3-6, PPh3-8 and PPh3-10 with ArB(OH)2 (Ar = Ph, p-NO2C6H4, p-MeOC6H4, 8-quinolyl and 3-pyridyl) and (ii) C(sp2),N oxazoline-derived complex PPh3-4 with pinacol esters of allyl- and benzylboronic acids occurred in a refluxing 4:1 mixture of dioxane-water in the presence of K3PO4 and afforded C(sp2)–C(sp3) coupling products in 46–89% yield. Desirable compounds with an C(sp3)–C(sp3) bond were isolated in 17–67% yield in the reactions of pinacol ester of benzylboronic acid with C(sp3),N complexes PPh3-6 and PPh3-8. The stereoselectivity of the transformation was investigated using reactions of p-NO2C6H4B(OH)2 with two diastereomeric complexes, (1S,2S,4R,Z)-12 and (1S,2R,4R,Z)-12, which were obtained from N,N-dimethylhydrazone of d-camphor, and had different absolute configurations of the chiral center attached to the metal. Both reactions yielded the same isomer, (1R,3R,4R,Z)-1,1-dimethyl-2-[1,7,7-trimethyl-(4-nitrophenyl)bicyclo[2.2.1]heptan-2-ylidene]hydrazine, as the major product. The X-ray crystallographic study of this product proved the R absolute configuration of the new chiral center suggested using 1H NMR data.

Transition Metal-Catalyzed Regioselective Direct C-H Amidation: Interplay between Inner- and Outer-Sphere Pathways for Nitrene Cross-Coupling Reactions.

Catalytic C-N bond cross-coupling reactions have been a subject of fundamental importance in synthetic organic and medicinal chemistry because amides and amines are ubiquitous motifs in natural products, functional materials, and pharmaceuticals. Since the pioneering works of Breslow and Mansuy on the metalloporphyrin-catalyzed direct hydrocarbon amidation using sulfonyliminoiodinane reagents, substantial development has been achieved toward practical and selective amination protocols. Notably, Du Bois's group developed the dirhodium(II,II) carboxylate catalytic system for direct C(sp3)-H amidations via Rh-sulfonyl nitrene intermediates. Yet, this protocol suffers from competitive alkene aziridination and is limited to electron-rich tertiary and ethereal C-H bonds; analogous direct amidation of arenes remained ineffective.This Account discusses our early effort to explore cyclopalladated complexes for ortho-selective C(aryl)-H amidations. While Buchwald-Hartwig amination cannot be directly applied to arenes, effective amidation of the 2-arylpyridines occurred when an external oxidant such as K2S2O8 was employed. Preliminary studies suggested that the amidation may proceed through reactive Pd-nitrene intermediates. Aiming to develop more diversified amidation protocols, we employed nosyloxycarbamates as nitrene precursors for the Pd-catalyzed ortho-amidation of N-pivalanilides. Likewise, we developed the ortho-selective amidation of benzoic acids to produce anthranilic acids, which are versatile precursors for many medicinally valuable heterocycles. In an attempt to expand the C(aryl)-N coupling reactions to amines, we studied the d6 piano-stool Cp*Rh(III) systems [Cp* = pentamethylcyclopentadienyl]. Our work established a sound reaction platform based on the electrophilic aminating reagents including N-chloroamines, hydroxyamides, and N-carboxyhydrazides for effective C(aryl)-N bond formation in aryl-metal complexes.Building upon the metal-nitrene reaction platform, we moved forward to examine γ-lactam synthesis by intramolecular carbonyl nitrene C(sp3)-H insertion. Noted that carbonyl nitrenes are prone to undergo Curtius-type rearrangement to form isocyanate; we found that the π-basic Ru(II) center effectively decomposes dioxazolones to afford the carbonyl nitrene for regioselective γ-C(sp3)-H insertion. With chiral diphenylethylenediamines (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the [(p-cymene)Ru(dpen)] complex catalyzed the decomposition of the dioxazolones to afford chiral γ-lactams by formal carbonyl nitrene C(sp3)-H insertion. Enantioselective nitrene insertion to allylic and propargylic C(sp3)-H bonds was also achieved with remarkable tolerance to the C═C and C≡C bonds. Notably, the selectivity of the [(p-cymene)Ru] system switched to C(aryl)-H bonds to give dihydroquinolinones when l-proline was employed as ligand. Recently, we aimed to address the regiocontrolled amidation of unactivated methylene C-H bonds using NiH catalyst. While tertiary and benzyl C-H bonds can be differentiated by their bond dissociation energies and steric properties, methylene groups making up the hydrocarbon skeleton display similar electronic and steric properties. In this context, we exploited the five-membered nickelacycle formation to terminate the NiH-mediated chain-walk isomerization, and the nickelacycle reacted with dioxazolones to furnish the C(sp3)-N bond at the γ-methylene position.This Account summarizes our contribution to the development of C-N bond cross-coupling reactions via C-H activation. By exploiting the inner-sphere and outer-sphere reaction pathways, we successfully developed regioselective protocols that target C(sp3)-H and C(aryl)-H bonds. The mechanistic underpinning of the selectivity of different C-H bonds and related studies on the affiliated catalytic systems will be discussed.

A new Pd(II) complex containing acetophenone oxime and 1,3-Bis(diphenylphosphino)propane ligands; crystal structure, catalytic activity, molecular docking and in vitro cytotoxic evaluation

A new palladium (II) complex of the type [Pd{C,N-C6H4{C(Me) = NOH}-2}(dppp)]ClO4 (2) has been prepared by the reaction of the cyclopalladated oxime complex [Pd{C,N-C6H4{C(Me) = NOH}-2}(μ-Cl)]2 (1) with 1,3-Bis(diphenylphosphino)propane (dppp). The new complex has been synthesized via a bridge-splitting reaction in the presence of NaClO4 under mild conditions. Complex 2 was fully characterized by elemental analysis (CHN), spectroscopic methods (IR, 1H-, 31P-, 13C NMR) and single-crystal X-ray diffraction analysis. The structure shows the palladium atom to be in a slightly distorted square-planar geometry surrounded by one C,N-chelating oxime ligand and one P,P-chelating dppp ligand forming five- and a six-membered metallocyclic rings, respectively. The catalytic activity of complex 2 has been evaluated using Suzuki cross coupling reactions. The coupled products of these reactions were obtained in good to excellent yields and purity, low catalyst loading and short reaction times. The cytotoxic activity of complexes 1 and 2 were comparatively studied against HeLa, A549, and 1321 N1 cell lines, which showed a greater efficiency of the mononuclear complex 2 over the binuclear complex 1. Finally, molecular docking simulation was employed as a computational method to investigate the interactions of complexes 1 and 2 with the protein involved in apoptosis.

The thiosulfate (S2O32−) ion; a neglected but simple hetero-donor ligand towards platinum(II), palladium(II) and nickel(II)

Reactions of the thiosulfate ligand (as sodium thiosulfate, Na2S2O3·5H2O) with phosphine complexes of the group 10 metals Ni(II), Pd(II) and Pt(II) resulted in five neutral thiosulfate complexes, [Ni(S2O3)(dppe)] (dppe = Ph2PCH2CH2PPh2), [Pd(S2O3)(dppe)], [Pd(S2O3)(dppf)] (dppf = Fe(C5H4PPh2)2), [Pd(S2O3)(PPh3)2] and [Pt(S2O3)(PPh3)2]. X-ray structure determinations of [Pd(S2O3)(dppf)], [Pd(S2O3)(PPh3)2] and [Pt(S2O3)(PPh3)2] confirmed that thiosulfate ligand coordinates as a bidentate chelating ligand via both sulfur and oxygen donor atoms. In addition, reactions of the thiosulfate ligand with dinuclear chloride-bridged cyclopalladated complexes gave four mononuclear anionic complexes [Pd(S2O3)(damp)]− (damp = N,N-dimethylbenzylamino, (CH3)2NCH2C6H4), [Pd(S2O3)(ptpy)]− (ptpy = p-tolylpyridyl), ]Pd(S2O3)(bzpy)]− (bzpy = 2-benzylpyridyl) and [Pd(S2O3))pap)]− (pap = 2-(phenylazo)phenyl). The structure of (Ph3PCH2Ph)[Pd(S2O3)(pap)] by X-ray crystallography revealed the ability of thiosulfate ligand to cleave the bridging chloride ligand on the starting complexes by acting as an S,O-donor chelating ligand. An ESI mass spectrometric investigation showed that the coordinated thiosulfate ligand undergoes fragmentation at elevated capillary exit voltages.

6-Membered cyclopalladated complex of 1-N-ferrocenylmethylindazole and its catalytic activity in cross-coupling Suzuki reactions

6-Membered cyclopalladated complex of 1-N-ferrocenylmethylindazole and its catalytic activity in cross-coupling Suzuki reactions

Palladium-Catalyzed Aminomethylative Oppolzer-Type Cyclization of Enynes: Access to Aminomethylated Benzofulvenes

A novel palladium-catalyzed Oppolzer-type cyclization reaction aided by the aminomethyl cyclopalladated complex has been developed, which provides rapid access to functionalized benzofulvenes with excellent stereoselectivity. The corresponding products can undergo Diels-Alder reaction with maleimides, providing a series of complex polycyclic compounds with excellent regio- and stereoselectivities.

Synthesis and biological evaluation of novel tetranuclear cyclopalladated complex bearing thiosemicarbazone scaffold ligand: Interactions with double‐strand DNA, coronavirus, and molecular modeling studies

AbstractThreading intercalators are a novel class of materials that carry two substituents along the diagonal positions of an aromatic ring. When bound to DNA, these substituents project out in DNA grooves. Tetranuclear complexes appear to be promising threading intercalators for developing therapeutics against cancer and viral infections that require high nucleic acid binding affinity. The objective of this work was to prepare the thiosemicarbazone scaffold ligand [4‐ClC6H4CHN=NC(S)NHPh] and tetranuclear cyclopalladated complex [Pd(4‐ClC6H4CHN=NC(S)NHPh)4] and to characterize the compounds by elemental analysis, 1D and 2D NMR, HRMS, and IR spectroscopy. The calf thymus DNA (CT‐DNA) binding properties of the compounds were investigated in vitro under simulated physiological conditions using UV–vis spectroscopy, emission spectral titration, methylene blue competitive binding, circular dichroism, DNA thermal denaturation, DNA binding, and coronavirus interactions using molecular simulation. The compounds showed cytotoxic effect against both human breast (MCF‐7) and colorectal (HCT116) cancer cells in a dose‐dependent manner. We demonstrated that the compounds are promising for DNA threading intercalation binders with large DNA binding constants on the order of 107 M−1 magnitude.

Catalytic Reactions Directed by a Structurally Well-Defined Aminomethyl Cyclopalladated Complex.

The introduction of N-containing moieties into feedstock molecules to build nitrogenated functional molecules has always been widely studied by the organic chemistry community. Progress in this field paves new roads to the synthesis of N-containing molecules, which are of significant importance in biological activities and play vital roles in pharmaceuticals and functional materials. Remarkable progress has been achieved in the field of transition metal-catalyzed C-N bond-forming reactions, typified by alkene hydroamination and the aza-Wacker reaction. However, the poisoning effect of electron-donating amine substrates on late transition metal catalysts presents a key impediment to these reactions, thus limiting the scope of amine substrates to electron-deficient amide derivatives. To address this problem, our group developed a palladium-aminomethyl complex with a three-membered palladacycle structure that allowed for the incorporation of electron-rich amine building blocks via C-C bond instead of C-N bond construction. This Account details the discovery of the well-defined aminomethyl cyclopalladated complex and recapitulates its applications for the catalysis of a series of aminomethylation reactions. We highlight how the understanding of the fundamental structural properties of the defined complex guided us toward tuning the reactivity of nucleophiles to initiate aminomethylation in different modes. Moreover, principles of designing and establishing further cascade reactions are also described.Aminomethyl cyclopalladated complexes can be prepared via the oxidative addition of aminals or N,O-acetals to Pd0 species. Thorough structural investigations by single-crystal X-ray diffraction analysis of the cyclopalladated complex suggest the presence of both aminomethylene-PdII (3-membered-ring) and Pd0-iminium (π-ligated) resonance forms, which indicates that both the palladium center and the methylene site are electrophilic. This is further verified by analysis of charge distribution. Two general types of reactions can be established, differing by the selective affinity of the nucleophiles to the two electrophilic positions, which is relevant to the "hardness suitability" of the nucleophiles with each electrophilic site. Softer nucleophiles such as alkenes prefer to attack the palladium center to initiate the reaction, mainly via migratory insertion into the Pd-C bond on the 3-membered ring with high strain. Through tandem β-hydride or reductive elimination, the Heck-type aminomethylation of styrenes, the aminomethylalkoxylation of electron-rich olefins, and even the aminomethylamination of allenes, dienes, enynes, and carbenoids with full atom-economy have been realized in line with this reaction mode. In contrast, harder nucleophiles tend to attack the harder electrophilic methylene site, leading to the aminomethylation of electron-deficient dienes. For secondary amines, a "C-N bond metathesis" process would be furnished through a reductive elimination, 1,3-proton transfer, and oxidative addition sequence. More intriguingly, when using appropriate "dinucleophile" substrates such as electron-rich amine-tethered dienes, sequential C-N bond metathesis and intramolecular insertion would occur to furnish Pd-catalyzed annulation reactions, which exhibits both the hard and soft nucleophile reactivities mentioned above. These transformations provide convenient methods for the preparation of N-containing molecules, such as amines, diamines, amino acetals, and multiple types of N-heterocycles.

Site-Isolated Azobenzene-Containing Metal-Organic Framework for Cyclopalladated Catalyzed Suzuki-Miyuara Coupling in Flow.

Sites isolation of active metals centers, systematically studied in homogeneous systems, has been an alternative to develop low metal consuming, highly active next generation catalysts in heterogeneous condition. Because of the high porosity and facile synthetic procedures, MOF-based catalysts are excellent candidates for heterogenization of well-defined homogeneous catalysts. Herein, we report the direct Pd coordination on the azobenzene linker within a MOF catalyst through a postsynthetic modification method for a Suzuki-Miyaura coupling reaction. The immobilized cyclopalladated complexes in MOFs were analyzed by a series of characterization techniques including XPS, PXRD, and deuterium NMR (2H NMR) spectroscopy. The heterogeneous nature of the catalyst as well as its stability were demonstrated though "hot filtration" and recycling experiments. Furthermore, we demonstrate that the MOF packed column promoted the reaction between phenyl boronic acid and bromobenzene under microflow conditions with a 85% yield continuously for 12 h. This work sheds light on the potential of site-isolated MOF catalysts in efficient, recyclable and continuous flow systems for industrial application.

Nanostructured Palladacycle and its Decorated Ag-NP Composite: Synthesis, Morphological Aspects, Characterization, Quantum Chemical Calculation and Antimicrobial Activity

We herein report the synthesis of nanostructured cyclopalladated complex and its nanosilver composite for the first time. The reaction between Schiff base ligand 4-methyl-N-(3,4-dimethoxybenzylidene)] benzenamine (L) and palladium acetate gave the cyclopalladted complex (Pd1) in nanoscale. Thermal treatment of silver oxalate with Pd1 resulted in the formation of novel nanostructured composite, silver nanoparticle-decorated palladacycle (Pd2). The synthesized compounds were characterized using spectroscopic analysis (FT-IR and 1H NMR), thermal analysis (TGA), XRD and morphological analysis (SEM and TEM). The spectral analysis revealed that complex Pd1 has dimeric structure bridged with acetate ligands between two monomers. SEM images exhibited that Ag-NPs loaded on complex surface in decorated form. TEM photographs showed the particle sizes of composite ≈ 29 nm. Quantum chemical analysis of ligand and complex Pd1 has been carried out by DFT/B3LYP method. There are two suggested isomers for cyclopalladated complex named Pd1 and Pd1* which are theoretically studied and correlated with practical results. HOMO, LUMO energy values, chemical hardness–softness, electronegativity and electrophilic index were calculated. The theoretical data obtained have been confirmed that the Pd1 isomer is more stable than Pd1* isomer which correlated well with practical results. The ligand and complexes screened for antimicrobial activity against five medically important microorganisms, namely Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli and Candida albicans. The results showed that complex Pd2 displayed the highest activity against the tested microorganisms.

Synthesis and characterization of mixed ligand cyclopalladates with 2-phenylpyridine and substituted phenanthrolines: Investigation into the hydroxylation reaction of 2-phenylpyridine

Mixed ligand cyclopalladated complexes with 2-phenylpyridine (ppy) and 2,9-dimethyl-1,10-phenanthroline (ncp), 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (bcp), 4,7-diphenyl-1,10-phenanthroline (bphen) were synthesized and characterized. The crystal structures of [Pd(ppy)(ncp)Cl] (1), [Pd(ppy)(ncp)Η2O]PF6·0.5(CH3CH2)O (3) and {[Pd(ppy)(ncp)]2(μ-Cl)}PF6 (4) were determined by single-crystal diffraction methods. In all cases, the results showed a pseudo-pentacoordinated palladium environment due to the anisobidentate binding of the 2,9-dimethyl-1,10-phenanthroline. The structures of the complexes in acetone solution were studied using NMR spectroscopic techniques, mass spectrometry and conductivity measurements. The results revealed the retention of their solid-state structure. The complexes (1), (4) and [Pd(ppy)(phen)]PF6, (6) were examined for their activity in the hydroxylation reaction of 2-phenylpyridine using NMP (N-methyl-2-pyrrolidone) and molecular oxygen as oxidant. The complex [Pd(ppyO)(phen)]PF6 (8), was isolated from the hydroxylation reaction mixture and could potentially imply that the reaction mechanism includes the formation of high-valent palladium species with Pd-OH bond(s).

The Exchange of Cyclometalated Ligands.

Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a cyclometalated compound and an incoming ligand that replaces a previously cyclometalated ligand to form a new metalacycle: + H-C*~Z ⇄ + H-C~Y. Originally discovered for PdII complexes with Y/Z = N, P, S, the exchange appeared to be a mechanistically challenging, simple, and convenient routine for the synthesis of cyclopalladated complexes. Over four decades it was expanded to cyclometalated derivatives of platinum, ruthenium, manganese, rhodium, and iridium. The exchange, which is also questionably referred to as transcyclometalation, offers attractive synthetic possibilities and assists in disclosing key mechanistic pathways associated with the C–H bond activation by transition metal complexes and C–M bond cleavage. Both synthetic and mechanistic aspects of the exchange are reviewed and discussed.

New Insights Into the Mechanism of Action of the Cyclopalladated Complex – CP2 in <i>Leishmania</i>: Calcium Dysregulation, Mitochondrial Dysfunction and Cell Death

Background: Leishmaniasis is a parasitic disease that affects millions of people and lacks new molecules for treatment. The current treatment is associated with high toxicity, a difficult administration route, and the emergence of resistant strains. These disadvantages raise the necessity to develop novel compounds with effective leishmanicidal activity and elucidate their action mechanism. Methods: To provide new information about of mechanism of action of the binuclear cyclopalladated complex [Pd(dmba)(µ-N3)]2 (CP2) in Leishmania, we have utilized two-dimensional SDS-PAGE for proteomic analyses, analyses of the progression of the cell cycle by flow cytometry. The measurement of reactive oxygen species (ROS) and mitochondrial membrane potential by fluorescence, live-cell Fura-2 Ca2+ imaging, and a dual acridine orange/ethidium bromide (AO/EB) staining method for the cell death mechanism. In vivo leishmanicidal activity has been performed in a golden hamster model. Findings: Dysregulation of parasite Ca2+ levels coming mainly from mitochondria, increasing ROS production and collapsing the Leishmania mitochondrial membrane potential. The presence of CP2 promotes apoptotic-like features in promastigotes six hours post-CP2-treatment. Exposure of parasites for 24 h or 48 h to CP2 leads to necrosis or directs programmed cell death (PCD)-committed cells toward necrotic-like destruction of cells. Besides, CP2 leads to arrests of cell cycle progression at S-phase, even in the absence of ROS production, and increases the expression of stress-related proteins, including calreticulin, Heat shock 10 kDa protein 1 (Hsp10), Hsp70, GRP78/BiP, and protein disulfide-isomerase (PDI) and cell detoxification proteins (trypanothione reductase, peroxiredoxin, tryparedoxin peroxidase). These studies provide new insight into the mechanism of action of CP2. When Leishmania infantum-infected Golden hamsters were treated for 15 days with 1·5 mg/Kg/day, CP2 caused a reduction in the parasite load of both liver and spleen by ~50%, which is similar to the leishmanicidal activity of amphotericin B. Interpretation: Our finding established the ability of CP2 to cause oxidative stress with disruption of mitochondrial Ca 2+ homeostasis of Leishmania, leading to other effects observed downstream to CP2-treatment. This new insight into the cyclopalladated complex's mechanism of action may have wider therapeutic applications targeting the parasite's mitochondria since structural modification to improve the leishmanicidal effect of CP2 may offer an alternative therapeutic agent for this neglected disease. Funding Information: This work was supported by the Sao Paulo Research Foundation (FAPESP) grants: #2016/05345-4, #2016/177115, #2017/03552-5 and #2018/23015-7; Programa de Apoio ao Desenvolvimento Cientifico da Faculdade de Ciencias Farmaceuticas da UNESP (PADC); and Funding from the Thomas P. Infusino Endowment at Rutgers University. AMAV (#2016/19289-9 and #2019/21661-1) and SV (#2016/18191-5) were supported by FAPESP. This study was financed in part by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) - Finance Code 001, IAPL, TGP, KBI, JMV. MARB, AVGN and MASG are recipienu of a Research Productivity Scholarship from the National Council for Research and Development (CNPq). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The Ethics Committee approved this study for Animal Experimentation of Sao Paulo State University (UNESP), the School of Pharmaceutical Sciences (CEUA/FCF/CAr, 18/2015 and 44/2015) in agreement with the guidelines of Sociedade Brasileira de Ciencia de Animais de Laboratorio (SBCAL) and Conselho Nacional de Controle da Experimentacao Animal (CONCEA).

Developing strong NIR absorption materials through linear planar π-conjugated cyclopalladated complex dimers.

Near-infrared absorption metal complexes (NIRMCs) have been traditionally associated with the π-expanded macrocycle structure. However, macrocyclic ligands suitable for NIRMCs require a laborious synthetic route, and are a limited few. Herein, we report a kind of NIRMC based on linear large planar π-conjugated cyclopalladated dimers, which can be obtained by a facile base-induced dimerization of corresponding monomers. These dimers show an intense absorption in the NIR region with ε770 nm = 2.5 × 105 cm-1 M-1, and display a fluorescence emission peak at ca. 910 nm. Quinoid thiophene methine (QTM) and the cyclopalladated structure are speculated to be the key factors for their strong NIR absorption, which provides a different perspective of preparing NIR absorption metal complexes.