Labile Ligands Research Articles

ChemInform Abstract: A Copper(II)‐Catalyzed, Sequential Michael‐Aldol Reaction for the Preparation of 1,2‐Dihydroquinolines.

AbstractMeCN functions as a labile ligand for the copper and as an agent to minimize the hydrolytic catalyst poisoning.

Electronic structure and molecular properties of paramagnetic hexanuclear Tantalum [Ta6X12Y6]3− (X and Y = F, Cl, Br, I) cluster compounds

Relativistic density functional calculations were carried out on several Tantalum cluster of the general formula [Ta6X12Y6]3−, with the aim to characterize and analyze their molecular structure and electronic properties, in order to gain more insights into their stability and reactivity. Herein are reported the geometrical parameters, electronic structures, excitation energies and magnetic properties, of a series of clusters that have been and have not been yet synthesized. The calculated Δg tensor shows that as the halide capping ligand become heavier the Δg tensor values increases due to spin–orbit effects. Through the use of the reactivity indexes it is shown that when the axial ligand is iodine it becomes the most reactive and labile ligand. The TD-DFT calculations on the complete [Ta6X12Y6]3− cluster family show good agreement with the available experimental data.

Studies into the Mechanism of CO-Induced N2 Cleavage Promoted by an Ansa-Hafnocene Complex and C–C Bond Formation from an Observed Intermediate

Carbonylation of the hafnocene dinitrogen complex, [Me(2)Si(η(5)-C(5)Me(4))(η(5)-C(5)H(3)-(t)Bu)Hf](2)(μ(2), η(2), η(2)-N(2)), yields the corresponding hafnocene oxamidide compound, arising from N(2) cleavage with concomitant C-C and C-N bond formation. Monitoring the addition of 4 atm of CO by NMR spectroscopy allowed observation of an intermediate hafnocene complex with terminal and bridging isocyanates and a terminal carbonyl. (13)C labeling studies revealed that the carbonyl is the most substitutionally labile ligand in the intermediate and that N-C bond formation in the bridging isocyanate is reversible. No exchange was observed with the terminal isocyanate. Kinetic data established that the conversion of the intermediate to the hafnocene oxamidide was not appreciably inhibited by carbon monoxide and support a pathway involving rate-determining C-C coupling of the isocyanate ligands. Addition of methyl iodide to the intermediate hafnocene resulted in additional carbon-carbon bond formation arising from CO homologation following nitrogen methylation. Similar reactivity with (t)BuNCO was observed where C-C coupling occurred upon cycloaddition of the heterocumulene. By contrast, treatment of the intermediate hafnocene with CO(2) resulted in formation of a μ-oxo hafnocene with two terminal isocyanate ligands.

Easy Access to Hydride Chemistry on a Tripodal P-Based Rhodium Scaffold

The TBPY-5 rhodium complex [(PhBP3)Rh(CH2═CH2)(NCMe)] (1; PhBP3 = PhB(CH2PPh2)3), which contains ethylene in the equatorial plane and a labile acetonitrile ligand at one of the axial positions, provides a simple entry into the chemistry of the fac-[P3Rh] scaffold. DFT calculations using the model compound [(MeB(CH2PMe2)3)Rh(CH2═CH2)(NCMe)] (1′) reproduce well the crystallographic geometry of 1 and converge to the isolated conformer, in which the strong π back-donation from the metal to the π* orbital of ethylene fixes it coplanar with the equatorial plane. Oxidation of 1 is electrochemically irreversible (at 0.080 V vs SCE), and 1 was effectively oxidized with [Cp2Fe]+ in acetonitrile to [(PhBP3)Rh(NCMe)3]2+. Reaction of 1 with hydrogen in toluene gives the dihydride [(PhBP3)Rh(H)2(NCMe)] (3), which loses acetonitrile to give the insoluble hydride [{(PhBP3)Rh(H)(μ-H)}2] (4), while 1 in THF with BHT (2,6-bis(1,1-dimethylethyl)-4-methylphenol) results in the mixed-valence paramagnetic hydride [{(PhBP3)Rh}2(...

The effect of varying carboxylate ligation on the electronic environment of N2Ox(x = 1–3) nonheme iron: A DFT analysis

Mononuclear nonheme iron oxygenase (MNO) enzymes contain a subclass of metalloproteins capable of catalyzing the O(2)-dependent hydroxylation of unactivated substrates at a ferrous ion center coordinated to a highly conserved His-His-Glu/Asp motif. These enzymes, which utilize additional reducing equivalents obtained from the decarboxylation of a coordinated α-ketoglutarate (αKG) cofactor, do not readily interact with O(2) in the absence of αKG binding. Density functional theory calculations with the B3LYP functional were performed to gain insight into the electrochemical behavior of three sets of Fe(II/III) complexes containing a core N, N, O facial binding motif in which the number of carboxylate ligands was systematically altered, to provide one, two (cis) or three (fac) labile sites. The calculated trend in Fe(II/III) reduction potentials was observed to parallel that observed in cyclic voltammetry experiments, showing a decrease in potential (stabilized oxidized state) with increasing carboxylate ligation. This trend does not appear to be the result of differential charge on the metal complex. Changes in the redox-active molecular orbital (RAMO) energy due to covalent effects dominate across the series of complexes when chloride is modeled as the labile ligand, with the π anti-bonding nature of the RAMO being an important factor. With water molecules as the labile ligands, however, a much steeper redox dependence on the number of carboxylate ligands is observed and this effect seems to be largely electrostatic in origin. Differential relaxation of the occupied molecular orbitals in the ferric complexes appears to contribute to the redox trend as well. Finally, these observations are placed in the context of MNO enzyme mechanisms.

CXCR4 chemokine receptor antagonists: nickel(ii) complexes of configurationally restricted macrocycles

Tetraazamacrocyclic complexes of transition metals provide useful units for incorporating multiple coordination interactions into a single protein binding molecule. They can be designed with available sites for protein interactions via donor atom-containing amino acid side chains or labile ligands, such as H(2)O, allowing facile exchange. Three configurationally restricted nickel(II) cyclam complexes with either one or two macrocyclic rings were synthesised and their ability to abrogate the CXCR4 chemokine receptor signalling process was assessed (IC(50) = 8320, 194 and 14 nM). Analogues were characterised crystallographically to determine the geometric parameters of the acetate binding as a model for aspartate. The most active nickel(II) compound was tested in several anti-HIV assays against representative viral strains showing highly potent EC(50) values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC(50) > 125 μM).

Synthesis of 1,2,3-tripnictolide anions by reaction of group 15 Zintl ions with acetylene. Isolation of [E3C2H2]− (E = P, As) and preliminary reactivity studies

Dimethylformamide solutions of K(3)E(7) (E = P, As) react with acetylene yielding the 1,2,3-tripnictolide anions [E(3)C(2)H(2)](-) (R = P (1), As (2)). Preliminary studies have shown that 1 and 2 displace labile ligands in [Ru(COD){η(3)-CH(3)C(CH(2))(2)}(2)] (COD = 1,5-cyclooctadiene) to yield the novel complexes [Ru(η(5)-E(3)C(2)H(2)){CH(3)C(CH(2))(2)}(2)}](-) (E = P (3), As (4)).

Cytotoxicity and Hydrolysis of trans-Ti(IV) Complexes of Salen Ligands: Structure–Activity Relationship Studies

Eleven bis(dimethylphenolato) Ti(IV) complexes of salen ligands with different steric and electronic properties due to different aromatic substituents at the ortho and para positions are reported, and their cytotoxicity toward HT-29 and OVCAR-1 cells and its dependence on hydrolytic behavior are discussed. Eight complexes of this series were analyzed by X-ray crystallography, confirming the trans geometry of the labile ligands with otherwise relatively similar coordination features to those of cis-salan analogues. Relatively high and similar hydrolytic stability is observed for all complexes, with t(1/2) values for labile ligand hydrolysis of 2-11 h in 10% D(2)O solutions. In contrast, varying cytotoxicities were achieved, identifying selected members as the first trans-Ti(IV) complexes reported as anticancer agents. Steric bulk all around the complex diminished the activity, where a complex with no aromatic substitutions is especially active and complexes substituted particularly at the ortho positions are mostly inactive, including ortho-halogenated and ortho-tert-butylated, with one exception of the ortho-methoxylated complex demonstrating appreciable activity. In contrast, para-halogenation provided the complexes of highest cytotoxic activity in this series (IC(50) as low as 1.0 ± 0.3 μM), with activity exceeding that of cisplatin by up to 15-fold. Reaction of a representative complex with ortho-catechol yielded a "cis"-Ti(IV) complex following rearrangement of the salen ligand on the metal center, with highly similar coordination features and geometry to those of the catecholato salan analogues, suggesting that the complexes operate by similar mechanisms and rearrangement of the salen ligand may occur upon introduction of a suitable chelating target. In additional cytotoxicity measurements, a salen complex was preincubated in the biological medium for varying periods prior to cell addition, revealing that marked cytotoxicity of the salen complex is retained for longer preincubation periods relative to known Ti(IV) complexes, suggesting that the hydrolysis products may also induce cytotoxic effects, thus reducing stability concerns.

ChemInform Abstract: Supramolecular Coordination: Self‐Assembly of Finite Two‐ and Three‐Dimensional Ensembles

AbstractReview: 840 refs.

A copper(II)-catalyzed, sequential Michael–aldol reaction for the preparation of 1,2-dihydroquinolines

A copper(II)-catalyzed, sequential Michael addition-aldol condensation reaction of N-carboxybenzyl-protected aminobenzaldehyde with various α,β-unsaturated N-acyl pyrroles is described. Substrate scope was found to include both aryl and aliphatic N-acyl pyrroles as the Michael acceptors, and isolated product yields as high as 93% were observed. The use of acetonitrile as the reaction solvent proved to be crucial for catalysis, both to function as a labile ligand for copper, as well as an agent to minimize hydrolytic catalyst poisoning.

ChemInform Abstract: Iridium‐Catalyzed Allylic Substitution

AbstractReview: 107 refs.

Gold(III) complexes with 2-substituted pyridines as experimental anticancer agents: Solution behavior, reactions with model proteins, antiproliferative properties

Gold(III) compounds form a family of promising cytotoxic and potentially anticancer agents that are currently undergoing intense preclinical investigations. Four recently synthesized and characterized gold(III) derivatives of 2-substituted pyridines are evaluated here for their biological and pharmacological behavior. These include two cationic adducts with 2-pyridinyl-oxazolines, [Au(pyoxR)Cl2][PF6], [pyoxR=(S)-4-benzyl-2-(pyridin-2-yl)-4,5-dihydrooxazole, I; (S)-4-iso-propyl-2-(pyridin-2-yl)-4,5-dihydrooxazole, II] and two neutral complexes [Au(N,N′OH)Cl2], III, and [Au(N,N′,O)Cl], IV, containing the deprotonated ligand N-(1-hydroxy-3-iso-propyl-2-yl)pyridine-2-carboxamide, N,N′H,OH, resulting from ring opening of bound pyoxR ligand of complex II by hydroxide ions. The solution behavior of these compounds was analyzed. These behave as classical prodrugs: activation of the metal center typically takes place through release of the labile chloride ligands while the rest of the molecule is not altered; alternatively, activation may occur through gold(III) reduction. All compounds react eagerly with the model protein cyt c leading to extensive protein metalation. ESI MS experiments revealed details of gold–cyt c interactions and allowed us to establish the nature of protein bound metal containing fragments. The different behavior displayed by I and II compared to III and IV is highlighted. Remarkable cytotoxic properties, against the reference human ovarian carcinoma cell lines A2780/S and A2780/R were disclosed for all tested compounds with IC50 values ranging from 1.43 to 6.18μM in the sensitive cell line and from 1.59 to 10.86μM in the resistant one. The common ability of these compounds to overcome cisplatin resistance is highlighted. The obtained results are thoroughly discussed in the frame of current knowledge on cytotoxic gold compounds.

Exploring binding site of human RBP4 towards discovery of novel inhibitor for treatment of cardiovascular diseases

AbstractRetinol binding proteins (RBPs) are transport proteins that act by solubilizing and protecting their labile ligands in aqueous spaces. In addition, RBPs have diverse and specific functions in regulating the disposition, metabolism and activities of retinoids. Elevated levels of retinol-binding protein 4 (RBP4) are observed in cardiovascular disease conditions, which prompts it as a potential drug target. Therefore, computational approach methods were implemented herein to design a novel inhibitor for RBP4. Crystal structure (2wq9) of RBP4 was retrieved and investigated to locate retinol binding site residues (Lys29, Pro32, Leu35, Phe36, Leu37, Phe45, Ala55, Ala57, Met73, Val74, Gly75, Met88, Try90, His104, Gln117, Arg121, Try133, Phe135, Phe137). Five existing inhibitors of RBP4 were explored against more than one million entries of the Ligand.Info metadatabase to create an in-house library of 2000 compounds. A ligand dataset was prepared using LigPrep and filtered based on Lipinski’s rule of five and reactive group constraints. The crystal structure was optimized and energy minimized applying OPLS force field in Maestro v9.2. Thirteen leads were found to have good binding affinity towards RBP4 through virtual screening workflow of Maestro. Lead 1, namely equilenin (-12.87 kcal/mol) which showed better XPG score was proposed as a potential RBP4 inhibitor. Analysis of docking complexes for the proposed lead revealed a stable hydrogen bond network with good van der Waal interactions and binding orientations. Thus, equilenin would be useful for developing potential drug molecules for cardiovascular diseases.

Unexpected Influence of Stereochemistry on the Cytotoxicity of Highly Efficient TiIV Salan Complexes: New Mechanistic Insights

The effect of stereochemistry on the cytotoxicity of highly active and hydrolytically stable N-methylated Ti(IV) salan complexes is reported. Four bis(isopropoxo) complexes incorporating N-methylated salan ligands with different aromatic substitution patterns have been prepared in racemic and optically active forms for the first time by ligand-to-metal chiral induction from trans-diaminocyclohexyl-based chiral ligands. The configuration of the metal center that derives from that of the ligand has an enormous influence on cytotoxicity, with the racemic mixture mostly being more active than the single enantiomers that are of either similar or different activity. This implies that the active species is a salan-bound heterochiral polynuclear compound, interacting with a chiral target. Four additional complexes of achiral salan and chiral labile sec-butoxo ligands, analyzed as racemic and as homochiral, revealed no influence of stereochemistry, supporting early dissociation of the labile ligands to give the polynuclear products.

Dinucleating Naphthyridine‐Based Ligand for Assembly of Bridged Dicopper(I) Centers: Three‐Center Two‐Electron Bonding Involving an Acetonitrile Donor

Unusual bonding: A ligand system that promotes formation of a rare μ-η1:η1 acetonitrile-bridged dicopper(I) complex (see picture) has been developed. The acetonitrile ligand is involved in a three-center two-electron bond supported by a cuprophilic interaction. The labile acetonitrile ligand can be substituted with xylyl isocyanide or CO.

Remote Effects of Axial Ligand Substitution in Heterometallic Cr≡Cr···M Chains

The heterometallic complexes CrCrM(dpa)(4)Cl(2) (dpa = 2,2'-dipyridylamide) featuring linear Cl-Cr≡Cr···M-Cl chains can regiospecifically be modified via axial ligand substitution to yield OTf-Cr≡Cr···M-Cl chains (OTf = triflate) with M being Fe, Mn, or Co. The effect of OTf substitution on the Cr side of the molecule has an unusual and profound structural impact on the square-pyramidal transition metal M. Specifically, elongation of the four equatorial M-N(py) bonds and the axial M-Cl bonds by 0.03 and 0.09 Å for Fe and 0.07 and 0.11 Å for Mn is observed. The longer M-Cl and M-N(py) bonds result from subtle interactions between the equatorial dpa ligand and the three metal ions. The equatorial dpa ligand responds to the introduction of the more labile OTf ligand at Cr by binding more strongly to this Cr ion which in turn weakens bonding to M. The ligand field experienced by M can be tuned by changing the Cr axial ligand, and this effect is observed in electrochemical measurements of the iron compounds.

Synthesis, nucleic acid binding and cytotoxicity of oligonuclear ruthenium complexes containing labile ligands

We report the synthesis, nucleic acid binding and cytotoxicity of the complexes [Ru(terpy)(Me2bpy)Cl]+, [Ru(terpy)(phen)Cl]+ and dinuclear [{Ru(terpy)Cl}2(μ-bbn)]2+ {where Me2bpy = 4,4′-dimethyl-2,2′-bipyridine; phen = 1,10-phenanthroline; and bbn = bis[4(4′-methyl-2,2′-bipyridyl)]-1,n-alkane, with n = 7, 10, 12, 14}. The complexes were isolated from the reaction of the [Ru(terpy)Cl3] precursor with the respective bidentate and di-bidentate bridging ligands. The time-course UV–Visible spectroscopy of the reaction of the mono- and dinuclear complexes with guanosine 5-monophosphate (GMP) showed the movement of the metal-to-ligand charge transfer (MLCT) band to lower wavelengths, accompanied by a hypochromism effect. The formation of the aqua complex and phosphate-bound intermediates in the reaction were detected by the time-course 1H NMR and 31P NMR experiments, which also demonstrated that the complex bound to the N7 guanine was the major product. The UV–Visible and 1H NMR studies showed no evidence of the interaction of the complexes with both adenosine 5-monophosphate (AMP) and cytidine 5-monophosphate (CMP). Cytotoxicity studies of these complexes against a murine leukemia L1210 cell line revealed that the dinuclear [{Ru(terpy)Cl}2(μ-bbn)]2+ complexes were significantly more cytotoxic than mononuclear [Ru(terpy)(Me2bpy)Cl]+. The [{Ru(terpy)Cl}2(μ-bb14)]2+ complex appeared to be the most active (IC50 = 4.2 μM).

Cytotoxic dinuclear titanium-salan complexes: Structural and biological characterization

Controlled hydrolysis of donor-substituted titanium-salan complexes led to the formation of well-defined dinuclear complexes. Structure determination by means of X-ray and NMR-studies revealed the presence of a single μ-oxo bridge and one labile alkoxide ligand per titanium center. Concomitant cytotoxicity assays of the isolated dinuclear complexes showed cytotoxicities in the low micro-molar region, surpassing in this respect even their monomeric ancestors, thus making them possible highly active metabolites of titanium-salan anti-cancer drugs.

Supramolecular coordination: self-assembly of finite two- and three-dimensional ensembles.

Supramolecular coordination: self-assembly of finite two- and three-dimensional ensembles.

Catalytic Properties of Low Oxidation State Iron Complexes in Cross‐Coupling Reactions: Anthracene Iron(−I) Complexes as Competent Catalysts

Catalyzing cross couplings: The catalytic activity of well-defined low-valent iron complexes in cross-coupling reactions has been investigated. The results show that labile ligands in the catalyst precursor are beneficial for high catalytic activity. Thus, anionic iron(−I) complexes with labile anthracene ligands are competent precatalysts for cross couplings that involve alkyl, aryl, and alkenyl electrophiles. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.