PESIN Conjugates for Multimodal Imaging: Can Multimerization Compensate Charge Influences on Cell Binding Properties? A Case Study.

Recently, anionic charges were found to negatively influence the in vitro gastrin-releasing peptide receptor (GRPR) binding parameters of dually radioisotope and fluorescent dye labeled GRPR-specific peptide dimers. From this, the question arose if this adverse impact on in vitro GRP receptor affinities could be mitigated by a higher valency of peptide multimerization. For this purpose, we designed two different hybrid multimodal imaging units (MIUs), comprising either one or two click chemistry-compatible functional groups and reacted them with PESIN (PEG3-BBN7-14, PEG = polyethylene glycol) dimers to obtain a dually labeled peptide homodimer or homotetramer. Using this approach, other dually labeled peptide monomers, dimers, and tetramers can also be obtained, and the chelator and fluorescent dye can be adapted to specific requirements. The MIUs, as well as their peptidic conjugates, were evaluated in terms of their photophysical properties, radiolabeling efficiency with 68Ga and 64Cu, hydrophilicity, and achievable GRP receptor affinities. Here, the hydrophilicity and the GRP receptor binding affinities were found to be especially strongly influenced by the number of negative charges and peptide copies, showing logD (1-octanol-water-distribution coefficient) and IC50 (half maximal inhibitory concentration) values of -2.2 ± 0.1 and 59.1 ± 1.5 nM for the homodimer, and -1.9 ± 0.1 and 99.8 ± 3.2 nM for the homotetramer, respectively. From the obtained data, it can be concluded that the adverse influence of negatively charged building blocks on the in vitro GRP receptor binding properties of dually labeled PESIN multimers can, at least partly, be compensated for by the number of introduced peptide binding motives and the used molecular design.

Isomeric Diruthenium Complexes Bridged by Deprotonated Indigo in cis and trans Configuration.

The doubly deprotonated form L2- of indigo=H2 L can bind two [Ru(acac)2 ] complex fragments in the cis (1) and trans configuration (2), as evidenced from crystal structure analysis. While the latter type of N,O; N' ,O' coordination has been observed earlier, for example, with [Ru(bpy)2 ]2+ , leading to two equivalent six-membered ring chelates, the cis arrangement in 1 is observed here for the first time in a dinuclear complex, producing one five-membered ring chelate with N,N' coordination and one seven-membered chelate with O,O' coordination. The different structures of the isomers result in differing electrochemical and spectroelectrochemical (EPR, UV-Vis-NIR) responses for various accessible charge states 1n and 2n , n=-, 0, +, 2+. The associated electronic structures were analyzed by DFT (structures, spin density) and TD-DFT calculations (electronic transitions), revealing mainly metal-based reduction but largely indigo ligand-based oxidation of both neutral precursors.

Non-innocence and mixed valency in tri- and tetranuclear ruthenium complexes of a heteroquinone bridging ligand.

The redox-active ligand 5,7,12,14-tetraazapentacene-6,13-quinone = L forms structurally characterised compounds with three (1) or four (2) [Ru(acac)2] complex fragments in which each of the metals is N,O-chelated. The new tris- and tetrakis-bidentate chelate compounds exhibit ruthenium centres bridged at about 4 Å by quinone O atoms which are then situated across the pentacene π system at about 6-8 Å distance. Several electron transfer processes were observed by voltammetry (CV, DPV) and the intermediates identified by EPR and UV-Vis-NIR spectroelectrochemistry. TD-DFT calculations were applied to assign the proper oxidation states within the multistep redox systems {(µn-L)[Ru(acac)2]n}k, n = 3 or 4, revealing both metal and ligand based electron transfer.

Organosilicon Radicals with Si-H and Si-Me Bonds from Commodity Precursors.

The cyclic alkyl(amino) carbene (cAAC) stabilized biradicals of composition (cAAC)2SiH2 (1), (cAAC)SiMe2-SiMe2(cAAC) (2), and (cAAC)SiMeCl-SiMeCl(cAAC) (3) have been isolated as molecular species. All the compounds are stable at room temperature for more than 6 months under inert conditions in the solid state. All radical species were fully characterized by single-crystal X-ray structure analysis and EPR spectroscopy. Furthermore, the structure and bonding of compounds 1-3 have been investigated by theoretical methods. Compound 1 contains the SiH2 moiety and this is the first instance, where we have isolated 1 without an acceptor molecule.

A structurally characterised redox pair involving an indigo radical: indigo based redox activity in complexes with one or two [Ru(bpy)2] fragments.

The reaction between indigo, H2Ind, and {Ru(bpy)2(EtOH)2}2+ in EtOH/NaOH produced the compounds [Ru(bpy)2(HInd)]ClO4 [1]ClO4, rac-{[Ru(bpy)2]2(µ-Ind)}(ClO4)2 [2](ClO4)2, and meso-{[Ru(bpy)2]2(µ-Ind)}(ClO4)3 [2](ClO4)3, which were structurally characterised, the latter as the first stable, isolable radical complex of indigo. The redox pair 22+/23+ showed little structural difference, as confirmed using DFT calculations. The redox series 1n and 2n were investigated using voltammetry and spectroelectrochemistry (EPR, UV-vis-NIR). Remarkably, the EPR results for 1, 12+, 2+ and 23+ revealed mostly ligand based spin in ruthenium(ii) complexes of the indigo-derived radical ligands HInd˙2-, HInd˙, Ind˙3- and Ind˙-, in agreement with the DFT calculated spin densities. The dominance of the frontier orbitals by the metal-stabilised indigo chromophore was also confirmed via the TD-DFT based assignment of near-infrared absorptions as intra-indigo or ligand-to-ligand charge transfer transitions.

Metal-Metal Bridging Using the DPPP Dye System: Electronic Configurations within Multiple Redox Series.

Redox series [LnRu(µ-DPPP)RuLn]k, H2DPPP = 2,5-dihydro-3,6-di-2-pyridylpyrrolo(3,4-c)pyrrole-1,4-dione and L = 2,4-pentanedionato (acac-), 2,2'-bipyridine (bpy), and 2-phenylazopyridine (pap), have been studied by voltammetry (CV, DPV), EPR, and UV-vis-NIR spectroelectrochemistry, supported by TD-DFT calculations. Crystal structure analysis and 1H NMR revealed oxidation states [(acac)2RuIII(µ-DPPP2-)RuIII(acac)2] and [(bpy)2RuII(µ-DPPP2-)RuII(bpy)2]2+ for the corresponding precursors, isolated as rac diastereomers. Oxidation was observed to occur mainly at the bridging ligand (DPPP2- → DPPP•-), whereas the site of reduction (DPPP, Ru, or L) depends on effects from the ancillary ligands L. The metal coordination of a derivative of the pigment forming 2,5-dihydro-pyrrolo(3,4-c)pyrrole-1,4-dione (DPP) dyes and the analysis of corresponding multistep redox series add to the previously recognized coordinative and electron transfer potential of dye molecules of the azo, indigo, anthraquinone, and formazanate type.

Isomeric Diruthenium Complexes of a Heterocyclic and Quinonoid Bridging Ligand: Valence and Spin Alternatives for the Metal/Ligand/Metal Arrangement.

5,7,12,14-Tetraazapentacene-6,13-quinone (L) reacts with 2 equiv of [Ru(acac)2(CH3CN)2] to form two linkage isomeric bis(chelate) compounds, [{RuII(acac)2}2(µ-L)], blue 1, with 5,6;12,13 coordination and violet 2 with 5,6;13,14 coordination. The linkage isomers could be separated, structurally characterized in crystals as rac diastereomers (ΔΔ/ΛΛ), and studied by voltammetry (CV, DPV), EPR, and UV-vis-NIR spectroelectrochemistry (meso-1, rac-2). DFT and TD-DFT calculations support the structural and spectroscopic results and suggest a slight energy preference (ΔE = 263 cm-1) for the rac-isomer 1 as compared to 2. Starting from the RuII-(µ-L0)-RuII configurations of 1 and 2 with low-lying metal-to-ligand charge transfer (MLCT) absorptions, the compounds undergo two reversible one-electron oxidation steps with open-shell intermediates 1+ (Kc = 4 × 104) and 2+ (Kc = 6 × 105). Both monocations display metal-centered spin according to EPR, but the DFT-calculated spin densities suggest a RuIII(µ-L•-)RuIII three-spin situation with opposite spin density at the bridging ligand for the meso form of 1+, estimated to lie 1887 cm-1 lower in energy than rac-1+, which is calculated with a Class II mixed-valent situation RuIII-(µ-L0)-RuII. A three-spin arrangement RuIII-(µ-L•-)-RuIII with negative spin density at one metal site is suggested by DFT for rac-2+ which is more stable by ΔE = 890 cm-1 than rac-1+. Reduction of 1 or 2 (Kc = 107-108) occurs mainly at the central bridging ligand with notable contributions (30%) from the metals in 1- and 2-. The mixed-valent RuIII(µ-L)RuII versus radical-bridged RuIII(µ-L•-)RuIII alternative is discussed comprehensively in comparison with related valence-ambiguous cases.

Different manifestations of enhanced π-acceptor ligation at every redox level of [Os(9-OP)L2]n, n = 2+, +, 0, - (9-OP- = 9-oxidophenalenone and L = bpy or pap).

The title complexes were isolated as structurally characterised compounds [OsII(9-OP)L2]ClO4, L = 2,2'-bipyridine (bpy) or 2-phenylazopyridine (pap), and were compared with ruthenium analogues. A reversible one-electron oxidation and up to three reduction processes were observed by voltammetry (CV, DPV) and spectroelectrochemistry (UV-vis-NIR, partially EPR). Supporting calculations (DFT, TD-DFT) were used to assess the oxidation state combinations of the different redox active ligands and of the metal, revealing the effects of Os versus Ru exchange and of bpy versus pap acceptor ligation. Several unexpected consequences of these variations were observed for members of the new osmium-containing redox series. Remarkably, the EPR results exhibit a clear dichotomy between the complex ion [OsIII(9-OP-)(bpy)2]2+ and the radical species [OsII(9-OP˙)(pap)2]2+, which has not been similarly observed for the analogous [RuIII(9-OP-)L2]2+ systems. This difference, unprecedented for 5dn systems, is attributed to the superior stabilisation of the OsII state by the strongly π-accepting pap ligands. The reduced forms [OsII(9-OP-)(pap˙-)(pap)] and [OsII(9-OP-)(pap˙-)2]- exhibit strong inter-ligand interactions, leading to spin isomers and electron hopping.

1,5-Diamido-9,10-anthraquinone, a Centrosymmetric Redox-Active Bridge with Two Coupled ß-Ketiminato Chelate Functions: Symmetric and Asymmetric Diruthenium Complexes.

The dinuclear complexes {(µ-H2L)[Ru(bpy)2]2}(ClO4)2 ([3](ClO4)2), {(µ-H2L)[Ru(pap)2]2}(ClO4)2 ([4](ClO4)2), and the asymmetric [(bpy)2Ru(µ-H2L)Ru(pap)2](ClO4)2 ([5](ClO4)2) were synthesized via the mononuclear species [Ru(H3L)(bpy)2]ClO4 ([1]ClO4) and [Ru(H3L)(pap)2]ClO4 ([2]ClO4), where H4L is the centrosymmetric 1,5-diamino-9,10-anthraquinone, bpy is 2,2'-bipyridine, and pap is 2-phenylazopyridine. Electrochemistry of the structurally characterized [1]ClO4, [2]ClO4, [3](ClO4)2, [4](ClO4)2, and [5](ClO4)2 reveals multistep oxidation and reduction processes, which were analyzed by electron paramagnetic resonance (EPR) of paramagnetic intermediates and by UV-vis-NIR spectro-electrochemistry. With support by time-dependent density functional theory (DFT) calculations the redox processes could be assigned. Significant results include the dimetal/bridging ligand mixed spin distribution in 3(3+) versus largely bridge-centered spin in 4(3+)-a result of the presence of Ru(II)-stabilizig pap coligands. In addition to the metal/ligand alternative for electron transfer and spin location, the dinuclear systems allow for the observation of ligand/ligand and metal/metal site differentiation within the multistep redox series. DFT-supported EPR and NIR absorption spectroscopy of the latter case revealed class II mixed-valence behavior of the oxidized asymmetric system 5(3+) with about equal contributions from a radical bridge formulation. In comparison to the analogues with the deprotonated 1,4-diaminoanthraquinone isomer the centrosymmetric H2L(2-) bridge shows anodically shifted redox potentials and weaker electronic coupling between the chelate sites.

Noninnocence of Indigo: Dehydroindigo Anions as Bridging Electron-Donor Ligands in Diruthenium Complexes.

Complexes of singly or doubly deprotonated indigo (H2Ind) with one or two [Ru(pap)2](2+) fragments (pap = 2-phenylazopyridine) have been characterized experimentally [molecular structure, voltammetry, electron paramagnetic resonance (EPR), and UV-vis-near-IR spectroelectrochemistry] and by time-dependent density functional theory calculations. The compound [Ru(pap)2(HInd(-))]ClO4 ([1]ClO4) was found to contain an intramolecular NH---O hydrogen bond, whereas [{Ru(pap)2}2(µ-Ind(2-))](ClO4)2 ([2](ClO4)2), isolated as the meso diastereoisomer with near-IR absorptions at 1162 and 991 nm, contains two metals bridged at 6.354 Å distance by the bischelating indigo dianion. The spectroelectrochemical study of multiple reversible reduction and oxidation processes of 2(n) (n = 4+, 3+, 2+, 1+, 0, 1-, 2-, 3-, 4-) reveals the stepwise addition of electrons to the terminal π-accepting pap ligands, whereas the oxidations occur predominantly at the anionic indigo ligand, producing an EPR-identified indigo radical intermediate and revealing the suitability of deprotonated indigo as a σ- and π-donating bischelating bridge.

Analysis of Redox Series of Unsymmetrical 1,4-Diamido-9,10-anthraquinone-Bridged Diruthenium Compounds.

The unsymmetrical diruthenium complexes [(bpy)2Ru(II)(µ-H2L(2-))Ru(III)(acac)2]ClO4 ([3]ClO4), [(pap)2RuII(µ-H2L(2-))Ru(III)(acac)2]ClO4 ([4]ClO4), and [(bpy)2Ru(II)(µ-H2L(2-))Ru(II)(pap)2](ClO4)2 ([5](ClO4)2) have been obtained by way of the mononuclear precursors [(bpy)2Ru(II)(H3L(-))]ClO4 ([1]ClO4) and [(pap)2Ru(II)(H3L(-))]ClO4 ([2]ClO4) (where bpy = 2,2'-bipyridine, pap = 2-phenylazopyridine, acac(-) = 2,4-pentanedionate, and H4L = 1,4-diamino-9,10-anthraquinone). Structural characterization by single-crystal X-ray diffraction and magnetic resonance (nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR)) were used to establish the oxidation state situation in each of the isolated materials. Cyclic voltammetry, EPR, and ultraviolet-visible-near-infrared (UV-vis-NIR) spectroelectrochemistry were used to analyze the multielectron transfer series of the potentially class I mixed-valent dinuclear compounds, considering the redox activities of differently coordinated metals, of the noninnocent bridge and of the terminal ligands. Comparison with symmetrical analogues [L2'Ru(µ-H2L)RuL2'](n) (where L' = bpy, pap, or acac(-)) shows that the redox processes in the unsymmetrical dinuclear compounds are not averaged, with respect to the corresponding symmetrical systems, because of intramolecular charge rearrangements involving the metals, the noninnocent bridge, and the ancillary ligands.

Correlated coordination and redox activity of a hemilabile noninnocent ligand in nickel complexes.

The compound [Ni(QM)2], QM = 4,6-di-tert-butyl-N-(2-methylthiomethylphenyl)-o-iminobenzoquinone, is a singlet diradical species with approximately planar configuration at the tetracoordinate metal atom and without any Ni-S bonding interaction. One-electron oxidation results in additional twofold Ni-S coordination (dNi-S ≈2.38 Å) to produce a complex cation of [Ni(QM)2](PF6) with hexacoordinate Ni(II) and two distinctly different mer-configurated tridentate ligands. The O,O'-trans arrangement in the neutral precursor is changed to an O,O'-cis configuration in the cation. The EPR signal of [Ni(QM)2](PF6) has a very large g anisotropy and the magnetic measurements indicate an S = 3/2 state. The dication was structurally characterized as [Ni(QM)2](ClO4)2 to exhibit a similar NiN2O2S2 framework as the monocation. However, the two tridentate (O,N,S) ligands are now equivalent according to the formulation [Ni(II)(QM(0))2](2+). Cyclic voltammetry reflects the qualitative structure change on the first, but not on the second oxidation of [Ni(QM)2], and spectroelectrochemistry reveals a pronounced dependence of the 800-900 nm absorption on the solvent and counterion. Reduction of the neutral form occurs in an electrochemically reversible step to yield an anion with an intense near-infrared absorption at 1345 nm (ε = 10,400 M(-1) cm(-1)) and a conventional g factor splitting for a largely metal-based spin (S = 1/2), suggesting a [(QM(·-))Ni(II)(QM(2-))](-) configuration with a tetracoordinate metal atom with antiferromagnetic Ni(II)-(QM(·-)) interactions and symmetry-allowed ligand-to-ligand intervalence charge transfer (LLIVCT). Calculations are used to understand the Ni-S binding activity as induced by remote electron transfer at the iminobenzoquinone redox system.

Solar cell sensitizer models [Ru(bpy-R)2(NCS)2] probed by spectroelectrochemistry.

Complexes [Ru(bpy-R)(2)(NCS)(2)], where R = H (1), 4,4'-(CO(2)Et)(2) (2), 4,4'-(OMe)(2) (3), and 4,4'-Me(2) (4), were studied by spectroelectrochemistry in the UV-vis and IR regions and by in situ electron paramagnetic resonance (EPR). The experimental information obtained for the frontier orbitals as supported and ascertained by density functional theory (DFT) calculations for 1 is relevant for the productive excited state. In addition to the parent 1, the ester complex 2 was chosen for its relationship to the carboxylate species involved for binding to TiO(2) in solar cells; the donor-substituted 3 and 4 allowed for better access to oxidized forms. Reflecting the metal-to-ligand (Ru → bpy) charge-transfer characteristics of the compounds, the electrochemical and EPR results for compounds 1-4 agree with previous notions of one metal-centered oxidation and several (bpy-R) ligand-centered reductions. The first one-electron reduction produces extensive IR absorption, including intraligand transitions and broad ligand-to-ligand intervalence charge-transfer transitions between the one-electron-reduced and unreduced bpy-R ligands. The electron addition to one remote bpy-R ligand does not significantly affect the N-C stretching frequency of the Ru(II)NCS unit. Upon oxidation of Ru(II) to Ru(III), however, the single N-C stretching band exhibits a splitting and a shift to lower energies. The DFT calculations serve to reproduce and understand these effects; they also suggest significant spin density on S for the oxidized form.

Ruthenium nitrosyl complexes with 1,4,7-trithiacyclononane and 2,2'-bipyridine (bpy) or 2-phenylazopyridine (pap) coligands. Electronic structure and reactivity aspects.

The present article describes ruthenium nitrosyl complexes with the {RuNO}(6) and {RuNO}(7) notations in the selective molecular frameworks of [Ru(II)([9]aneS(3))(bpy)(NO(+))](3+) (4(3+)), [Ru(II)([9]aneS(3))(pap) (NO(+))](3+) (8(3+)) and [Ru(II)([9]aneS(3))(bpy)(NO˙)](2+) (4(2+)), [Ru(II)([9]aneS(3))(pap)(NO˙)](2+) (8(2+)) ([9]aneS(3) = 1,4,7-trithiacyclononane, bpy = 2,2'-bipyridine, pap = 2-phenylazopyridine), respectively. The nitrosyl complexes have been synthesized by following a stepwise synthetic procedure: {Ru(II)-Cl} → {Ru(II)-CH(3)CN} → {Ru(II)-NO(2)} → {Ru(II)-NO(+)} → {Ru(II)-NO˙}. The single-crystal X-ray structure of 4(3+) and DFT optimised structures of 4(3+), 8(3+) and 4(2+), 8(2+) establish the localised linear and bent geometries for {Ru-NO(+)} and {Ru-NO˙} complexes, respectively. The crystal structures and (1)H/(13)C NMR suggest the [333] conformation of the coordinated macrocyclic ligand ([9]aneS(3)) in the complexes. The difference in π-accepting strength of the co-ligands, bpy in 4(3+) and pap in 8(3+) (bpy < pap) has been reflected in the ν(NO) frequencies of 1945 cm(-1) (DFT: 1943 cm(-1)) and 1964 cm(-1) (DFT: 1966 cm(-1)) and E°({Ru(II)-NO(+)}/{Ru(II)-NO˙}) of 0.49 and 0.67 V versus SCE, respectively. The ν(NO) frequency of the reduced {Ru-NO˙} state in 4(2+) or 8(2+) however decreases to 1632 cm(-1) (DFT: 1637 cm(-1)) or 1634 cm(-1) (DFT: 1632 cm(-1)), respectively, with the change of the linear {Ru(II)-NO(+)} geometry in 4(3+), 8(3+) to bent {Ru(II)-NO˙} geometry in 4(2+), 8(2+). The preferential stabilisation of the eclipsed conformation of the bent NO in 4(2+) and 8(2+) has been supported by the DFT calculations. The reduced {Ru(II)-NO˙} exhibits free-radical EPR with partial metal contribution revealing the resonance formulation of {Ru(II)-NO˙}(major)↔{Ru(I)-NO(+)}(minor). The electronic transitions of the complexes have been assigned based on the TD-DFT calculations on their DFT optimised structures. The estimated second-order rate constant (k, M(-1) s(-1)) of the reaction of the nucleophile, OH(-) with the electrophilic {Ru(II)-NO(+)} for the bpy derivative (4(3+)) of 1.39 × 10(-1) is half of that determined for the pap derivative (8(3+)), 2.84 × 10(-1) in CH(3)CN at 298 K. The Ru-NO bond in 4(3+) or 8(3+) undergoes facile photolytic cleavage to form the corresponding solvent species {Ru(II)-CH(3)CN}, 2(2+) or 6(2+) with widely varying rate constant values, (k(NO), s(-1)) of 1.12 × 10(-1) (t(1/2) = 6.2 s) and 7.67 × 10(-3) (t(1/2) = 90.3 s), respectively. The photo-released NO can bind to the reduced myoglobin to yield the Mb-NO adduct.

Stabilising a quinonoid-bridged dicopper(I) complex by use of a dppf (dppf = (diphenylphosphino)ferrocene) backbone.

An unprecedented quinonoid-bridged dicopper(I) complex is described together with its redox, EPR and structural properties, which indicate a non-innocent role of the zwitterion-derived bridging ligand.