Unsubstituted Ligand Research Articles

Novel ligands from direct benzylic functionalisation of tris(2-pyridylmethyl)amine.

Tris-(2-pyridylmethyl)amines (TPA or TPMA) are polipyrydine-based ligands extensively used in catalysis and supramolecular chemistry due their capability to form stable tetradentate complexes with a large variety of metals. The unsubstituted ligand, which is also commercially available, can be synthesised by consecutive alkylation of a picoline or by reductive amination of a pyridine aldehyde. In this article, we report a novel synthetic method which opens to the post-functionalisation of these ligands in the benzylic position. This novel derivatization strategy, beside providing synthetic access to novel structures and functions, has been used to prepare a series of metal complexes which have been tested in photochemical hydrogen evolution.

Periodic Trends in the Stabilization of Actinyls in Their Higher Oxidation States Using Pyrrophen Ligands.

Owing to the prominent existence and unique chemistry of actinyls, their complexation with suitable ligands is of significant interest. The complexation of high-valent actinyl moieties (An = U, Np, Pu and Am) with the acyclic sal-porphyrin analogue called "pyrrophen" (L(1)) and its dimethyl derivative (L(2)) with four nitrogen and two oxygen donor atoms was studied using relativistic density functional theory. Based on the periodic trends, the [UVO2-L(1)/L(2)]1- complexes show shorter bond lengths and higher bond orders that increase across the series of pentavalent actinyl complexes mainly due to the localization of the 5f orbitals. Among the hexavalent complexes, the [UVIO2-L(1)/L(2)] complexes have the shortest bonds. Following the uranyl complex, due to the plutonium turn, the [AmVIO2-L(1)/L(2)] complexes exhibit comparable properties with those of the former. Charge analysis suggests the complexation to be facilitated through ligand-to-metal charge transfer (LMCT) mainly through σ donation. Thermodynamic feasibility of complexation was modeled using hydrated actinyl moieties in aqueous medium and was found to be spontaneous. The dimethylated pyrrophen (L(2)) shows higher magnitudes of thermodynamic parameters indicating increased feasibility compared to the unsubstituted ligand (L(1)). Energy decomposition analysis (EDA) along with extended transition-state-natural orbitals for chemical valence theory (ETS-NOCV) analysis shows that the dominant electrostatic contributions decrease across the series and are counteracted by Pauli repulsion. Slight but considerable covalency is provided to hexavalent actinyl complexes by orbital contributions; this was confirmed by molecular orbital (MO) analysis that suggests strong covalency in americyl (VI) complexes. In addition to the pentavalent and hexavalent actinyl moieties, heptavalent actinyl species of neptunyl, plutonyl, and americyl were studied. Beyond the influence of the charges, the geometric and electronic properties point to the stabilization of neptunyl (VII) in the pyrrophen ligand environment, while the others shift to a lower (+VI) and relatively stable OS on complexation.

Binuclear Cobalt Paddlewheel-Type Complexes: Relating Metal-Metal Bond Lengths to Formal Bond Orders.

Paddlewheel-type complexes are prominent among experimentally known binuclear cobalt complexes and incorporate substituted formamidinate, guanidinate, and carboxylate ligands in digonal, trigonal, and tetragonal arrays around the bimetallic core. Such complexes are modeled here by density functional theory using unsubstituted ligands, extending the whole set to incorporate a variety of metal oxidation states and spin multiplicities. The DFT results for ground state cobalt-cobalt bond lengths and ground state spin multiplicity of the model complexes are often quite close to the experimental results for the corresponding substituted complexes. The three series of complexes often exhibit parallel trends with regard to effects of change in the metal oxidation state and spin multiplicity. The formamidinate and guanidinate series show marked resemblances. The lowered symmetry in many model trigonal complexes implies that such deviations in the experimentally known congeners arise from the inherent electronic structure. For ground state species, the DFT results provide Co-Co bond orders (BOs) from MO occupancy considerations. Further, using a revised electron bookkeeping method, Co-Co formal bond order (fBO) values from 0.0 to 2.0 are assigned to all of the 85 complexes studied. The computed Co-Co bond lengths fall into distinct ranges according to the formal bond order values (from 0.5 to 2).

The Significance of Halogen Bonding in Ligand-Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor.

Recently, a computational approach combining a structure–activity relationship library containing pairs of halogenated ligands and their corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was developed and used to search for amino acids frequently targeted by halogen bonding, also known as XB hot spots. However, the analysis of ligand–receptor complexes with halogen bonds obtained by molecular docking provides a limited ability to study the role and significance of halogen bonding in biological systems. Thus, a set of molecular dynamics simulations for the dopamine D4 receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand–receptor complex by halogen bonding.

Amino Acid Hot Spots of Halogen Bonding: A Combined Theoretical and Experimental Case Study of the 5-HT7 Receptor.

A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in a 5-HT7R as a case study. The procedure identified two sets of hot spots, extracellular (D2.65, T2.64, and E7.35) and transmembrane (C3.36, T5.39, and S5.42), which were further verified by a synthesized library of halogenated arylsulfonamide derivatives of (aryloxy)ethylpiperidines. It was found that a halogen bond formed between T5.39 and a bromine atom at 3-position of the aryloxy fragment caused the most remarkable, 35-fold increase in binding affinity for 5-HT7R when compared to the nonhalogenated analog. The proposed paradigm of halogen bonding hot spots was additionally verified on D4 dopamine receptor showing that it can be used in rational drug design/optimization for any protein target.

Tuning of the properties of a picolinic acid-based bispidine ligand for stable copper(II) complexation

The synthesis of the hexadentate bispidine-picolinate ligand L with two tertiary amine, two para-methoxy-substituted pyridine donors (p-OMe) and a picolinate group is reported, together with its NiII, CoII, CuII and ZnII coordination chemistry. The X-ray crystal structures of the CuII and ZnII complexes confirm that the geometries are very similar to those of the unsubstituted ligand. The increased nucleophilicity of the p-OMe substituted pyridine groups leads to a significant decrease in the metal-pyridine bond length but, due to the rigidity of the adamantane-derived bispidine backbone, the other metal-donor bonds are slightly elongated, and this leads to a larger degree of axial distortion, which augments the preference of the ligand for the Jahn-Teller-active CuII center. The structural effects are supported by the dd-electronic and EPR spectra, which indicate that, for CoII, NiII and CuII, the overall ligand field strengths of the unsubstituted ligand L′ and the p-OMe-substituted derivative L are very similar, and for CuII the in-plane ligand field is significantly stronger for the p-OMe-substituted ligand L. The MII/I redox potentials with the optimized ligand L are generally more negative for the CoII, NiII and CuII complexes, indicating that the oxidized form of the complexes takes more profit of the increase in complex stability. For CuII this is analyzed on the basis of the potentiometrically determined stability constants and their correlation with the redox potentials of the substituted and unsubstituted bispidines together with a large series of published data with other ligand systems. It emerges that L is a very selective CuII ligand with a great potential for radiopharmaceutical applications.

Synthesis and Characterization of Iron(II) Complexes with a BPMEN‐Type Ligand Bearing π‐Accepting Nitro Groups

In this paper, we describe the synthesis, characterization, and stability studies of new FeII complexes prepared with the ligand N,N′‐dimethyl‐N,N′‐bis(4‐nitropyridin‐2‐ylmethyl)ethane‐1,2‐diamine (L42NO2). The properties of these complexes were probed by magnetic, spectroscopic, and electrochemical techniques and compared with those of the parent complexes prepared with the unsubstituted ligand N,N′‐dimethyl‐N,N′‐bis(pyridin‐2‐ylmethyl)ethane‐1,2‐diamine (BPMEN or L42). The para functionalization of the pyridine moieties with π‐accepting nitro groups increases the ligand‐field strength and the Lewis acidity of the metal center without altering the stability of the complex.

Paramagnetic Resonance of Cobalt(II) Trispyrazolylmethanes and Counterion Association.

Paramagnetic resonance studies (EPR, ESEEM, ENDOR, and NMR) of a series of cobalt(II) bis-trispyrazolylmethane tetrafluoroborates are presented. The complexes studied include the parent, unsubstituted ligand (Tpm), two pyrazole-substituted derivatives (4Me and 3,5-diMe), and tris(1-pyrazolyl)ethane (Tpe), which includes a methyl group on the apical carbon atom. NMR and ENDOR establish the magnitude of 1H hyperfine couplings, while ESEEM provides information on the coordinated 14N. The data show that the pyrazole 3-position is more electron rich in the Tpm analogues, that the geometry about the apical atom influences the magnetic resonance, and that apical atom geometry appears more fixed in Tpm than in Tp. NMR and ENDOR establish that the BF4- counterion remains associated in fluid solution. In the case of the Tpm3,5Me complex, it appears to associate in solution, in the same position it occupies in the X-ray structure.

Synthetic and Computational Studies on the Rhodium-Catalyzed Hydroamination of Aminoalkenes.

The influence of ligand structure on rhodium-catalyzed hydroamination has been evaluated for a series of phosphinoarene ligands. These catalysts have been evaluated in a set of catalytic intramolecular Markovnikov hydroamination reactions. The mechanism of hydroamination catalyzed by the rhodium(I) complexes in this study was examined computationally, and the turnover-limiting step was elucidated. These computational studies were extended to a series of theoretical hydroamination catalysts to compare the electronic effects of the ancillary ligand substituents. The relative energies of intermediates and transition states were compared to those of intermediates in the reaction catalyzed by the unsubstituted catalyst. The experimental difference in the reactivities of electron-rich and electron-poor catalysts was compared to the computational results, and it was found that the activity for the electron-poor catalysts predicted from the reaction barriers was overestimated. Thus, the analysis of the catalysts in this study was expanded to include the binding preference of each ligand, in comparison to that of the unsubstituted ligand. This information accounts for the disparity between observed reactivity and the calculated overall reaction barrier for electron-poor ligands. The ligand-binding preferences for new ligand structures were calculated, and ligands that were predicted to bind strongly to rhodium generated catalysts for the experimental catalytic reactions that were more reactive than those predicted to bind more weakly.

Systematic dismantling of a carefully designed PCcarbeneP pincer ligand via C–C bond activations at an iridium centre

An electron-rich PCsp2P ligand, incorporating N,N-dimethylamino groups para to the anchoring carbene donor of the ligand, was prepared and coordinated to iridium, producing the iridium carbene chloride 2. This species undergoes facile reaction with N2O to afford an iridaepoxide complex, 3, in which an oxygen atom has been transferred to the Ir=C bond. The rate of this reaction is significantly faster than that observed for the less electron rich, unsubstituted ligand. However, further reaction of 3 involving cleavage of one of the ligand C–C bonds was observed, producing the bis-phosphine chorido complex 4. This process was accelerated by the presence of H2. Heating 4 under H2 resulted in hydrogenolysis of the ortho-metalated phosphine ligand to give a hydrido complex (5) and decarbonylation of the acyl phosphine ligand to give, finally, Vaska’s complex analog 6. All compounds were fully characterized, and the sequence represents the dismantling of the PCsp2P ligand framework.

Extending the family of stable heavier carbenes: New tetrylenes based on N,N,O-ligands

A series of novel heavier carbene analogs 3–8, MeN(CH2CH2NTs)(CH2CR2O)M (M=Ge (3, R=H; 4, R=Ph), Sn (5, R=H; 6, R=Ph), Pb (7, R=H; 8, R=Ph)), was prepared by the interaction of M[N(SiMe3)2]2 (M=Ge, Sn, Pb) with substituted N,N,O-ligands, 1 and 2, MeN(CH2CH2NHTs)(CH2CR2OH) (1, R=H; 2, R=Ph). All the compounds were investigated by IR and multinuclear NMR spectroscopy and it was established that in a solution tin and lead compounds are agglomerated. An X-ray diffraction analysis of 3 revealed the monomeric structure with three-coordinated Ge atom. In contrast to germylenes, plumbylenes are associated in solid state. In the crystalline phase, the steric hindrance affects the degree of association. Thus, lead derivative 7 based on unsubstituted ligand, 1, forms dimers with strong bridging Pb–O bonding which further crystallize into chains. On contrary, plumbylene 8 based on phenyl substituted ligand, 2, is monomeric and only weak Pb⋯OSO contacts are observed is the solid state.

Synthesis and extraction results of new halide terminated 2-alkyl-p-tert-butylcalix[4]arenes bearing phosphine oxides or ketones on the narrow rim

The synthesis of lower rim tetraphosphorylated and tetraketone calix[4]arenes with haloalkyl groups tethered to a single methylene bridge and their utilization as extraction agents for rare earth elements are reported. Synthesis of these new functionalized calix[4]arene species has been achieved in good to modest yields, and extraction of nine lanthanide nitrates has been explored using these novel calix[4]arene species. The tetraphosphorylated calix[4]arenes show better lanthanide extraction efficiency than their ketone counterparts, especially for europium (III). These experiments demonstrate that inclusion of a substituent tethered to the methylene bridge does not significantly reduce the extraction efficiency of these new calix[4]arene ligands as compared to similar unsubstituted ligands in literature, making them important precursors in the development of functionalized stationary phases for separation of lanthanides. Development of similar CMPO-bearing narrow rims and new solid-phase extraction materials for the solid–liquid separation of lanthanides remains the subject of future work.

Benzo[7]annulene-based GluN2B selective NMDA receptor antagonists: Surprising effect of a nitro group in 2-position.

Benzo[7]annulen-7-amines 7 without further polar substituents have been reported as conformationally restricted Ro 25-6981 analogs and show unexpectedly high GluN2B affinity. Herein the corresponding 2-NO2 derivatives 8 were synthesized and pharmacologically evaluated. NO2 derivatives 8 show 5- to 10-fold higher GluN2B affinity than the unsubstituted ligands 7. Docking studies of ligands 7c and 8c reveal an important contribution of the 2-NO2-substituent in determining the binding pose and modulating the GluN2B affinity.

Crystal structure of di-chlorido-(4,11-dimethyl-1,4,8,11-tetra-aza-bicyclo-[6.6.2]hexa-deca-ne)iron(III) hexa-fluorido-phosphate.

The title compound, [FeCl2(C14H30N4)]PF6, contains Fe(3+) coordinated by the four nitro-gen atoms of an ethyl-ene cross-bridged cyclam macrocycle and two cis chloride ligands in a distorted octa-hedral environment. In contrast to other similar compounds this is a monomer. Inter-molecular C-H⋯Cl inter-actions exist in the structure between the complex ions. Comparison with the mononuclear Fe(2+) complex of the same ligand shows that the smaller Fe(3+) ion is more fully engulfed by the cavity of the bicyclic ligand. Comparison with the μ-oxido dinuclear complex of an unsubstituted ligand of the same size demonstrates that the methyl groups of 4,11-dimethyl-1,4,8,11-tetra-aza-bicyclo-[6.6.2]hexa-decane prevent dimerization upon oxidation.

First hyperpolarizability of Ru-half-sandwich complexes: The effect of halogen atom substitution on the ancillary ligand

The first hyperpolarizability (β) of a series of half-sandwich Ru complexes with a mercaptobenzothiazole ligand bearing a halogen atom substitution in the para-position has been investigated by hyper-Rayleigh scattering and quantum chemical calculations. The heterocyclic ligand with a bromine atom in the para position makes it a very good donor and charge flows to the Ru center enhancing the β value of the complex by a factor of 2 compared to the complex with the ligand without the halogen substitution. The resonance (+R) and the inductive (-I) effects exerted by the halogen atom in the para position push electrons in opposing directions in the complex. For the Br and Cl atoms the resonance effect dominates which enables the ligand to donate electrons to the metal center thereby increasing the hyperpolarizability whereas for the fluorine atom, the inductive effect is dominant which reduces the charge flow to the metal and the hyperpolarizability drops even below that of the unsubstituted ligand. This unprecedented halogen atom effect on β of metal complexes is reported.

Synthesis and characterization of homoleptic chromium(III) complexes containing pyridine-2-thionato ligands and of the co-crystal (1:1) bis(pyridine-2-thionato)(pyridine-2-dithionato) chromium(III) tris(pyridine-2-thionato) chromium(III)

The reaction of [Cr(CO)6] with a series of heterocyclic bidentate (N,S) ligands in refluxing mesitylene afforded the homoleptic trischelate complexes [Cr(3-Me3SipyS)3] (2), [Cr(3-CF3pyS)3] (3) and [Cr(5-CF3pyS)3] (4), where R-pyS stands for the anion of the corresponding substituted pyridine-2-thione ligand. Studies in the solid state by X-ray diffraction showed that the reaction with the unsubstituted ligand HpyS yielded the compound [Cr(pyS)3]/[Cr(pyS)2(pySS)] (1), which is a two-component co-crystal comprising the homoleptic species [Cr(pyS)3] (1a) and the heteroleptic species [Cr(pyS)2(pySS)] (1b), in a 1:1 ratio. While the structure of the species [Cr(pyS)3] (1a) is analogous to that of other homoleptic compounds, [Cr(RpyS)3], the species [Cr(pyS)2(pySS)] (1b) is an unusual heteroleptic complex containing both pyridine-2-thionate and pyridine-2-dithionate ligands. All of the compounds obtained were characterized by microanalysis and FAB spectrometry, and by IR and UV–Vis spectroscopies. X-ray studies showed that in all cases the metal is in a distorted octahedral environment with the heterocyclic ligand acting as a bidentate (N,S) chelate system. The supramolecular organization in complexes (1) and (2) through hydrogen bonding, weak C–H⋯π and π–π interactions was analyzed.

Solid State Structural Variations in Copper(II) Complexes of Open-Chain and Macrocyclic Malonamide-Derived Ligands

An analysis of the molecular structure of the copper(II) complexes with open-chain and macrocyclic malonamide-derived tetradentate ligands based on single crystal X-ray diffraction study of four copper(II) complexes [CuL1(H2O)]·4H2O, [CuL2(H2O)], [CuL3(H2O)], and [CuL4(H2O)] (H2L1 = 1,4,8,11-tetraazaundecane-5,7-dione, H2L2 = 13-methyl-13-nitro-1,4,8,11-tetraazacyclotetradecane-5,7-dione, H2L3 = 1,4,8,11-tetraazacyclotetradecane-5,7-dione, and H2L4 = 1,4,8,11-tetraazacyclotridecane-5,7-dione) as well as on published data regarding related compounds revealed that the violations of planarity of the metal-amide fragments are due almost exclusively to the deviation of the copper(II) ion from the amide plane. Both the deviation of the copper(II) ion from the amide plane and the angle between amide planes in the 6-membered malonamide ring are strongly affected by substituents with minimal values observed in the complexes of unsubstituted ligands. The deviation of the copper(II) ion from the basal plane of donor...

Polycyclic Azoniahetarenes: Assessing the Binding Parameters of Complexes between Unsubstituted Ligands and G-Quadruplex DNA

Polycyclic azoniahetarenes were employed to determine the effect of the structure of unsubstituted polyaromatic ligands on their quadruplex-DNA binding properties. The interactions of three isomeric diazoniadibenzo[b,k]chrysenes (4 a-c), diazoniapentaphene (5), diazoniaanthra[1,2-a]anthracene (6), and tetraazoniapentapheno[6,7-h]pentaphene (3) with quadruplex DNA were examined by DNA melting studies (FRET melting) and fluorimetric titrations. In general, penta- and hexacyclic azoniahetarenes bind to quadruplex DNA (K(b) ≈10(6) M(-1)) even in the absence of additional functional side chains. The binding modes of 4 a-c and 3 were studied in more detail by ligand displacement experiments, isothermal titration calorimetry, and CD and NMR spectroscopy. All experimental data indicate that terminal π stacking of the diazoniachrysenes to the quadruplex is the major binding mode; however, because of different electron distributions of the π systems of each isomer, these ligands align differently in the binding site to achieve ideal binding interactions. It is proposed that tetraazonia ligand 3 binds to the quadruplex by terminal stacking with a small portion of its π system, whereas a significant part of the bulky ligand most likely points outside the quadruplex structure, and is thus partially placed in the grooves. Notably, 3 and the known tetracationic porphyrin TMPyP4 exhibit almost the same binding properties towards quadruplex DNA, with 3 being more selective for quadruplex than for duplex DNA. Overall, studies on azonia-type hetarenes enable understanding of some parameters that govern the quadruplex-binding properties of parent ligand systems. Since unsubstituted ligands were employed in this study, complementary and cooperative effects of additional substituents, which may interfere with the ligand properties, were eliminated.

A SAR Study of Novel Antiproliferative Ruthenium and Osmium Complexes with Quinoxalinone Ligands in Human Cancer Cell Lines

A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC(50) values of 6-60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate.

Synthesis and Evaluation of Lipophilic BTBP Ligands for An/Ln Separation in Nuclear Waste Treatment: The Effect of Alkyl Substitution on Extraction Properties and Implications for Ligand Design

AbstractFour new 6,6′‐bis(1,2,4‐triazin‐3‐yl)‐2,2′‐bipyridine (BTBP) ligands, which contain either additional alkyl groups on the pyridine rings or seven‐membered aliphatic rings attached to the triazine rings, have been synthesized, and the effects of the additional alkyl substitution in the 4‐ and 4′‐positions of the pyridine rings on their extraction properties with LnIII and AnIII cations in simulated nuclear waste solutions have been studied. The speciation of ligand 13 with some trivalent lanthanide nitrates was elucidated by 1H NMR spectroscopic titrations and ESI‐MS. Although 13 formed both 1:1 and 1:2 complexes with LaIII and YIII, only 1:2 complexes were observed with EuIII and CeIII. Quite unexpectedly, both alkyl‐substituted ligands 12 and 13 showed lower solubilities in certain diluents than the unsubstituted ligand CyMe4‐BTBP. Compared to CyMe4‐BTBP, alkyl‐substitution was found to decrease the rates of metal‐ion extraction of the ligands in both 1‐octanol and cyclohexanone. A highly efficient (DAm > 10) and selective (SFAm/Eu > 90) extraction was observed for 12 and 13 in cyclohexanone and for 13 in 1‐octanol in the presence of a phase‐transfer agent. The implications of these results for the design of improved extractants for radioactive waste treatment are discussed.