Protonation Of Ligand Research Articles

Novel Tridentate Hydrazone of Heterocyclic N‐oxide and Its Transition Metal Complexes: Evaluation of DNA/BSA Binding Interactions, In Vitro and In Silico Biological Properties

AbstractNovel hydrazone ligand 2‐(2‐(2‐hydroxy‐5‐methoxybenzylidene) hydrazinecarbonyl) pyridine 1‐oxide was synthesized and characterized by spectral analyses. The assessment of number of dissociable protons in ligand and evaluation of corresponding values of pKa and the stability constants for M(II)‐Ligand systems (M (II) = Cu, Co, Ni and Zn) in 30% DMF‐water medium were done by adopting pH‐metric method following Irving‐ Rossotti technique. To understand the chelation properties of hydrazone ligand, its contour maps of frontier molecular orbitals and their energies were computed using HyperChem 7.5 tools. The synthesized metal complexes of above hydrazone with Cu (II), Co (II), Ni (II) and Zn (II) were characterized with spectral and analytical techniques such as; FT‐IR, 1H‐NMR, LC‐MS, TGA, UV‐Vis, FE‐SEM‐EDX and ESR. The tridentate and dibasic nature of title ligand is ascertained from pH‐metric studies as well as through the analyses of analytical and spectral data of complexes. The CT‐DNA binding studies conducted adopting absorption and fluorescence titrations with metal complexes and ligand inferred their binding affinity through the mode of intercalation. The evaluated antioxidant and cytotoxicity properties revealed higher efficacy of copper complex. Furthermore, investigations employing molecular docking studies revealed non‐covalent bonding interactions of synthesized compounds with chosen protein target CDK2.

Enhancing HDAC Inhibitor Screening: Addressing Zinc Parameterization and Ligand Protonation in Docking Studies.

Precise binding free-energy predictions for ligands targeting metalloproteins, especially zinc-containing histone deacetylase (HDAC) enzymes, require specialized computational approaches due to the unique interactions at metal-binding sites. This study evaluates a docking algorithm optimized for zinc coordination to determine whether it could accurately differentiate between protonated and deprotonated states of hydroxamic acid ligands, a key functional group in HDAC inhibitors (HDACi). By systematically analyzing both protonation states, we sought to identify which state produces docking poses and binding energy estimates most closely aligned with experimental values. The docking algorithm was applied across HDAC 2, 4, and 8, comparing protonated and deprotonated ligand correlations to experimental data. The results demonstrate that the deprotonated state consistently yielded stronger correlations with experimental data, with R2 values for deprotonated ligands outperforming protonated counterparts in all HDAC targets (average R2 = 0.80 compared to the protonated form where R2 = 0.67). These findings emphasize the significance of proper ligand protonation in molecular docking studies of zinc-binding enzymes, particularly HDACs, and suggest that deprotonation enhances predictive accuracy. The study's methodology provides a robust foundation for improved virtual screening protocols to evaluate large ligand libraries efficiently. This approach supports the streamlined discovery of high-affinity, zinc-binding HDACi, advancing therapeutic exploration of metalloprotein targets. A comprehensive, step-by-step tutorial is provided to facilitate a thorough understanding of the methodology and enable reproducibility of the results.

Ligand protonation leads to highly fluorescent boronium cations.

Fluorophores that respond to external stimuli, such as changes in pH, have utility in bio-imaging and sensing applications. Almost all pH-responsive fluorophores rely on complex syntheses and the use of pH-responsive functional groups that are peripheral to the fluorophore framework. In this work, pH-responsive boron-containing heterocycles based on tridentate acyl pyridylhydrazone ligands were prepared. These non-emissive heterocycles were synthesized in three steps from inexpensive, commercially available reagents without the use of chromatography or air-sensitive reagents. Treatment with acid resulted in protonation of the boron-bound methylamine donor and efficient blue photoluminescence. Experimental and computational analysis revealed that protonation changed the geometric structure of the heterocycles and prevented photoluminescence quenching associated with photoinduced electron transfer. This work demonstrates a new approach for the design of fluorophores with potential applications in biological imaging.

Grafting Of Group 6 Imido–Alkyl Complexes on Silica: Mo vs. W

Grafting of the isostructural imido–alkyl complexes M(=NMes)2(CH2CMe2Ph)2 (M = Mo (1), W (2); Mes = 2,4,6-Me3C6H2) onto the surface of SiO2 partially dehydroxylated at 700 °C and physicochemical study (mass balance, IR, EA, SSNMR) of resulting materials 1s and 2s are presented. While for molybdenum complex, grafting primarily proceeds via cleavage of the alkyl group, protonation of the imido ligand becomes a predominant pathway for the tungsten counterpart. The catalytic activity of 1s and 2s in oxo/imido heterometathesis is also determined and compared with the previously reported systems.

Diimine–Dioxime Acenaphthene Cobalt Complexes: Characterization of the Novel cis Coordination Mode

AbstractDuring the synthesis of a new family of diimine–dioxime acenaphthene cobalt complexes a novel cis coordination mode was observed for (DABn)Co(Py)Br (4), along with the expected trans coordination mode for [(DAEn)Co(L)2]BPh4 (2). The new coordination mode for this class of compounds is fully characterized. We explore the influence of linker length, ligand protonation, and supporting ligands on the preference for the cis vs. trans coordination mode using experimental and computational methods. Increased flexibility, increased acidity, and large supporting ligands all support the preference for the cis coordination mode.

High-Nuclearity Polyoxometalate-Based Metal-Organic Frameworks for Photocatalytic Oxidative Cleavage of C-C Bond.

High-nuclearity polyoxometalate (POM) clusters are attractive building blocks (BBs) for the synthesis of metal-organic frameworks (MOFs) due to their high connectivity and inherently multiple metal centers as functional sites. This work demonstrates a strategy of step-wise growth on ring-shaped [P8W48O184]40- precursor, which produced two new high-nuclearity polyoxotungstates, a half-closed [H16P8W58O218]32- {W58} and a fully-closed [H16P8W64O236]32- {W64}. By in situ synthesis, unique MOFs of copper triazole-benzoic acid (HL) complexes incorporating the negatively-charged {W58} and {W64} as nodes, {Cu11(HL)9W58} HNPOMOF-1 and {Cu9(HL)9W64} HNPOMOF-2, were constructed by delicately tuning the reaction conditions, mainly solution pH, which controls the formation of {W58} and {W64}, and at the same time the protonation of triazole-benzoic acid ligand thus its coordination mode to copper ion that creates the highest nuclearity POM-derived MOFs reported to date. HNPOMOF-1 features 3D framework possessing cage-like cavities filled with exposed carboxyl groups, while the inherent 2D layer-like HNPOMOF-2 allows for facile exfoliation into ultrathin nanosheets, and the resulted HNPOMOF-2NS exhibits superior activity towards photocatalytic oxidative cleavage of C-C bond for a series of lignin models. This work not only provides a strategy to build high-nuclearity POM cluster-based frameworks, but also demonstrates their great potential as functional materials for green catalysis.

Single-Step Synthesis of An Ideal Chain Antiferromagnet [H2(4,4'-bipyridyl)](H3O)2Fe2F10 with Spin S=5/2.

One-dimensional (1D) magnets are of great interest owing to their intriguing quantum phenomena and potential application in quantum computing. We successfully synthesized an ideal antiferromagnetic spin S=5/2 chain compound [H2(4,4'-bpy)](H3O)2Fe2F10 (4,4'-bpy=4,4'-bipyridyl) 1, using a single-step low-temperature hydrothermal method under conditions that favors the protonation of the bulky bidentate ligand 4,4'-bpy. Compound 1 consists of well-separated (Fe3+-F-)∞ chains with a large Fe-F-Fe angle of 174.8°. Both magnetic susceptibility and specific heat measurements show that 1 does not undergo a magnetic long-range ordering down to 0.5 K, despite the strong Fe-F-Fe intrachain spin exchange J with J/kB=-16.2(1) K. This indicates a negligibly weak interchain spin exchange J'. The J'/J value estimated for 1 is extremely small (<2.8×10-6), smaller than those reported for all other S=5/2 chain magnets. Our hydrothermal synthesis incorporates both [H2(4,4'-bpy)]2+ and (H3O)+ cations into the crystal lattice with numerous hydrogen bonds, hence effectively separating the (Fe3+-F-)∞ spin chains. This single-step hydrothermal synthesis under conditions favoring the protonation of bulky bidentate ligands offers an effective synthetic strategy to prepare well-separated 1D spin chain systems of magnetic ions with various spin values.

Single‐Step Synthesis of An Ideal Chain Antiferromagnet [H2(4,4′‐bipyridyl)](H3O)2Fe2F10 with Spin S=5/2

AbstractOne‐dimensional (1D) magnets are of great interest owing to their intriguing quantum phenomena and potential application in quantum computing. We successfully synthesized an ideal antiferromagnetic spin S=5/2 chain compound [H2(4,4′‐bpy)](H3O)2Fe2F10 (4,4′‐bpy=4,4′‐bipyridyl) 1, using a single‐step low‐temperature hydrothermal method under conditions that favors the protonation of the bulky bidentate ligand 4,4′‐bpy. Compound 1 consists of well‐separated (Fe3+−F−)∞ chains with a large Fe−F−Fe angle of 174.8°. Both magnetic susceptibility and specific heat measurements show that 1 does not undergo a magnetic long‐range ordering down to 0.5 K, despite the strong Fe−F−Fe intrachain spin exchange J with J/kB=−16.2(1) K. This indicates a negligibly weak interchain spin exchange J′. The J′/J value estimated for 1 is extremely small (&lt;2.8×10−6), smaller than those reported for all other S=5/2 chain magnets. Our hydrothermal synthesis incorporates both [H2(4,4′‐bpy)]2+ and (H3O)+ cations into the crystal lattice with numerous hydrogen bonds, hence effectively separating the (Fe3+−F−)∞ spin chains. This single‐step hydrothermal synthesis under conditions favoring the protonation of bulky bidentate ligands offers an effective synthetic strategy to prepare well‐separated 1D spin chain systems of magnetic ions with various spin values.

Quantum refinement in real and reciprocal space using the Phenix and ORCA software.

X-ray and neutron crystallography, as well as cryogenic electron microscopy (cryo-EM), are the most common methods to obtain atomic structures of biological macromolecules. A feature they all have in common is that, at typical resolutions, the experimental data need to be supplemented by empirical restraints, ensuring that the final structure is chemically reasonable. The restraints are accurate for amino acids and nucleic acids, but often less accurate for substrates, inhibitors, small-molecule ligands and metal sites, for which experimental data are scarce or empirical potentials are harder to formulate. This can be solved using quantum mechanical calculations for a small but interesting part of the structure. Such an approach, called quantum refinement, has been shown to improve structures locally, allow the determination of the protonation and oxidation states of ligands and metals, and discriminate between different interpretations of the structure. Here, we present a new implementation of quantum refinement interfacing the widely used structure-refinement software Phenix and the freely available quantum mechanical software ORCA. Through application to manganese superoxide dismutase and V- and Fe-nitrogenase, we show that the approach works effectively for X-ray and neutron crystal structures, that old results can be reproduced and structural discrimination can be performed. We discuss how the weight factor between the experimental data and the empirical restraints should be selected and how quantum mechanical quality measures such as strain energies should be calculated. We also present an application of quantum refinement to cryo-EM data for particulate methane monooxygenase and show that this may be the method of choice for metal sites in such structures because no accurate empirical restraints are currently available for metals.

Dynamic, multi-color, multi-level stimulus-responsive luminescence in a co-crystallized coordination polymer: Modulation of energy transfer by acid-induced ligand protonation and photo-induced radical generation

Dynamic, multi-color, multi-level stimulus-responsive luminescence in a co-crystallized coordination polymer: Modulation of energy transfer by acid-induced ligand protonation and photo-induced radical generation

Synthesis and Characterization of Diacylthiourea and Diacylthioureato Cu(I) Complexes

A series of six disubstituted diacylthioureas 1,3‐ and 1,4‐C6H4[C(O)NHC(S)NR1R2]2 (L1‐6) were synthesized with varied Rn substituents (R1 = R2 = Et for L1‐2; R1 = R2 = Bn for L3‐4; R1 = iPr and R2 = Ph for L5 (1) and L6 (2)). Treatment of Ln with Cu(I) halide precursors CuX(PPh3)3 (X = Cl, Br, I) produced the discrete binuclear adducts Ln[CuX(PPh3)2]2 (3‐11 and 14‐16; n = 1‐3 and 6) by binding to Cu(I) centres via the monodentate‐S mode. In contrast, L4 and L5 yielded only the chloride products of binuclear L4[CuCl(PPh3)2]2 (12) and mononuclear L5CuCl(PPh3)2 (13), respectively, with one S arm in the latter remaining dangling, while bromide or iodide analogues were not available for L4 and L5, possibly due to the steric hindrance imposed by larger halide anions or bulky isopropyl substituents. The reactions of Ln with nitrate [Cu(NO3)(PPh3)2]led to the double‐deprotonation of ligand protons to generate dianions Ln' (1,3‐/1,4‐C6H4[C(O)NC(S)NR1R2]22‐) and led to the consequent formation of binuclear diacylthioureato Cu(I) complexes Ln'[Cu(PPh3)2]2 (n=1 (17), 2 (18), 4 (19)) via the κ‐O,S‐bidentate mode. The obtained ligands and complexes were spectroscopically and structurally characterized. These Cu(I) products (3‐19) were experimentally used as catalysts for the oxidation of 1‐phenylethanol.

Changing Mechanisms for CO2 Reduction to Formate Via Protonation of the Catalyst

Electrochemical reduction reaction of CO2 (CO2RR) is a promising method to transform CO2 to useful products for consumption such as formic acid, carbon monoxide, or methane. Simply increasing the driving force of a catalytic process to speed up the rate of CO2 reduction is unviable because of the competing Hydrogen Evolution Reaction (HER) pathway and of increased energy cost. Controlling the reactivity of active intermediates is of substantial importance for such processes. [Fe4N(CO)12]− is a formate selective electrocatalyst previously studied by our group and was modified through protonation and replacement of several CO ligands with triethylphosphines (PEt3) to synthesize [HFe4N(PEt3)4(CO)8] . This PEt3 substituted, pre-protonated analog of [Fe4N(CO)12]− exhibits altered rates compared to a non-protonated analog which we attribute to a switch in mechanism. We further explore explanations for different rates despite similar “active intermediates” and similar driving force using Cyclic Voltammetry (CV).

DGA-grafting pyridine for ultra-selective and prior extraction of 99TcO4− from simulated spent nuclear fuel

Selective and prior extraction of 99TcO4- ahead of uranium and plutonium separation is a beneficial strategy for the modern nuclear fuel cycle. Herein, a novel DGA-grafting pyridine ligand BisDODGA-DAPy (L1) was tailored for the efficient separation of TcO4- from simulated spent nuclear fuel based on the selectivity of pyridine and synergistic effect of diglycolamide (DGA) group. Compared to the ligands BisDOSCA-DAPy (L2) and BisDODGA-MPDA (L3) with similar structure, BisDODGA-DAPy (L1) demonstrated the better separation performance including good extraction efficiency, reusability, and high loading capacity for TcO4- under high acidic medium. The interactions of the ligands with Tc(VII)/Re(VII) have been investigated in detail using FT-IR, 1H NMR titration, UV-Vis spectrophotometric titration, ESI-HRMS and DFT simulations. The extraction mechanism affected by the protonation of ligand was elucidated under different acidity. BisDODGA-DAPy (L1) demonstrated the ultra-selective extraction ability for TcO4- from simulated spent nuclear fuel. The maximum SFTc/U and SFTc/Pu values were up to 1.29×104 and 5.08×103, respectively. In the presence of 9×104-fold excess of NO3-, the extraction of TcO4- was almost unaffected. Moreover, the good radiolytic stability further highlights the promising potential of this ligand for 99Tc separation. DFT calculation revealed the dominant role of DAPy and DODGA in TcO4- extraction, providing the theoretical evidence for BisDODGA-DAPy (L1) to selectively bind TcO4- over NO3-.

Structure and Dynamic Rearrangements of the Pt2dba3 and Pd2dba3 Complexes in Solution.

Although the tris(dibenzylideneacetone)diplatinum complex (Pt2dba3) is an important source of Pt(0) used in catalysis and materials science, its structure has not yet been fully elucidated. A thorough study of the three-dimensional structure of Pt2dba3 and its dynamic behavior in solution was carried out using NMR spectroscopy methods at a high field (600 MHz) and molecular modeling. The complex was shown to contain three dba ligands in the s-cis,s-trans, s-trans,s-cis, and s-trans,s-trans conformations, which are uniformly oriented around the Pt2 backbone. In solution, the Pt2dba3 and Pd2dba3 complexes undergo rapid dynamic rearrangements, as evidenced by the exchange between the signals of the olefin protons of various dba ligands in the EXSY NMR spectra. According to the experimental measurements, the activation energies of the rearrangements were estimated to be 19.9 ± 0.2 and 17.9 ± 0.2 kcal/mol for the platinum and palladium complexes, respectively. Three possible mechanisms for this chemical exchange process were considered within the framework of DFT calculations. According to the calculated data, M2dba3 complexes undergo fluxional isomerization involving successive rotations of the dihedral angles formed by the carbonyl group and the C═C bond. Dissociation of dba ligands does not occur within these processes.

External Trigger Free Charge Switchable Cationic Ligands in the Design of Safe and Effective Universal Heparin Antidote.

Thrombosis, the formation of blood clots within a blood vessel, can lead to severe complications including pulmonary embolism, cardiac arrest, and stroke. The most widely administered class of anticoagulants is heparin-based anticoagulants such as unfractionated heparin, low-molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA-approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin-binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies.

Elucidating the Structure of the Eu‐EDTA Complex in Solution at various Protonation States

Ethylenediaminetetraacetic acid (EDTA), which has two amine and four carboxylate protonation sites, forms stable complexes with lanthanide ions. This work analyzes the coordination structure, in atomic resolution, of the Eu3+ ion complexed with EDTA in all its protonation states in aqueous solution. Eu‐EDTA complexes were modeled using classical molecular dynamics (MD) simulations using force field parameters optimized with ab initio molecular dynamics (AIMD) simulations. Structures from the MD simulations were used to predict extended X‐ray absorption fine structure (EXAFS) spectra and compared with EXAFS measurements of the Eu3+ aqua ion and Eu‐EDTA complexes at pH 3 and 11. This work details how Eu‐EDTA complex coordination structures change with increasing protonation of the EDTA ligand in the complex, from the tightly bound unprotonated complex to the unbinding of the fully protonated EDTA ligand from the Eu3+ ion as both become solvated by water. Agreement between predicted and measured EXAFS spectra supports the findings from simulation.

Front Cover: Structural Changes to the Gd‐DTPA Complex at Varying Ligand Protonation State (Eur. J. Inorg. Chem. 6/2024)

Front Cover: Structural Changes to the Gd‐DTPA Complex at Varying Ligand Protonation State (Eur. J. Inorg. Chem. 6/2024)

Specificity of hexarhenium cluster anions for synthesis of Mn2+-based nanoparticles with lamellar shape and pH-induced leaching for specific organ selectivity in MRI contrasting

The present work demonstrates the structure variation of hexarhenium anionic cluster units [{Re6S8}(CN)(6-n)(OH)n]4- (n=0, 2, 4) as the strategy to develop Mn2+-containing nanoparticles (NPs) exhibiting pH-dependent leaching. The dicyanotetrahydroxo complex [{Re6S8}(CN)2(OH)4]4- is the optimal for the synthesis of the Mn2+-based NPs with a lamellar shape exhibiting the pH-dependent aggregation and magnetic relaxation behavior. The pH-dependent behavior of the NPs derives from the easy protonation of the apical hydroxo ligands of [{Re6S8}(CN)2(OH)4]4- cluster, which triggers partial leaching of Mn2+ ions and aggregation of the NPs driven by the surface neutralization. The in vivo MRI scanning of the mice intravenously injected with the NPs indicates the preferable accumulation of the lamellar NPs within mouse intestine over liver and kidneys. This differs from the spherical NPs constructed from [{Re6Se8}(CN)6]4- units, which provide the preferable brightening of mouse liver over kidneys and intestine.

X-ray absorption and emission spectroscopy of N2S2 Cu(II)/(III) complexes.

This study investigates the influence of ligand charge on transition energies in a series of CuN2S2 complexes based on dithiocarbazate Schiff base ligands using Cu K-edge X-ray absorption spectroscopy (XAS) and Kβ valence-to-core (VtC) X-ray emission spectroscopy (XES). By comparing the formally Cu(II) complexes [CuII(HL1)] (HL12- = dimethyl pentane-2,4-diylidenebis[carbonodithiohydrazonate]) and [CuII(HL2)] (HL22- = dibenzyl pentane-2,4-diylidenebis[carbonodithiohydrazonate]) and the formally Cu(III) complex [CuIII(L2)], distinct changes in transition energies are observed, primarily attributed to the metal oxidation state. Density functional theory (DFT) calculations demonstrate how an increased negative charge on the deprotonated L23- ligand stabilizes the Cu(III) center through enhanced charge donation, modulating the core transition energies. Overall, significant shifts to higher energies are noted upon metal oxidation, emphasizing the importance of scrutinizing ligand structure in XAS/VtC XES analysis. The data further support the redox-innocent role of the Schiff base ligands and underscore the criticality of ligand protonation levels in future spectroscopic studies, particularly for catalytic intermediates. The combined XAS-VtC XES methodology validates the Cu(III) oxidation state assignment while offering insights into ligand protonation effects on core-level spectroscopic transitions.

Exploring metal carbamates as precursors for the synthesis of metal-organic frameworks.

In the synthesis of metal-organic frameworks (MOFs), the choice of the metal precursor plays a key role because of the influence that it can exert on the crystallization kinetics. The present work explores the use of metal-carbamato complexes for the synthesis of benchmark MOFs, namely HKUST-1 and UiO-66. Cu2(O2CNEt2)4·2NHEt2 and Zr(O2CNEt2)4, prepared using straightforward CO2 fixation reactions starting from the corresponding metal chlorides and diethylamine, were employed as metal precursors for MOF formation. The synthesis conditions, including the solvent, temperature, and ligand protonation degree, were systematically investigated, revealing metal carbamates as highly reactive precursors due to their prompt release of CO2 and amine upon reaction with protic species, i.e., the polycarboxylic linkers. This property of metal carbamates allowed us to identify room temperature protocols to achieve MOFs with comparable properties to those obtained using traditional metal precursors. Subsequent optimization of the reaction conditions led to the design of a one-pot synthetic strategy for HKUST-1, starting directly from copper(II) chloride and diethylamine under a CO2 atmosphere. The MOFs were characterized using various techniques, including powder X-ray diffraction, N2 sorption analysis, 1H nuclear magnetic resonance spectroscopy, and CHN elemental analysis, and compared to reference samples prepared according to literature procedures.