Frederick M. MacDonnell

Synthesis of free and ruthenium coordinated 5,6-diamino-1,10-phenanthroline

Abstract A new preparative route to 5,6-diamino-1,10-phenanthroline is described which triples the isolated yields found in existing syntheses (67% vs. 22% from 1,10-phenanthroline) and utilizes mild reaction conditions. The method is general and can even be used on chiral metal complexes containing the appropriate starting material/ligand, 1,10-phenanthroline-5,6-dione, with retention of stereochemistry.

Regression of Lung Cancer by Hypoxia-Sensitizing Ruthenium Polypyridyl Complexes

The ruthenium (II) polypyridyl complexes (RPC), Δ-[(phen)2Ru(tatpp)]Cl2 (Δ-[3]Cl2) and ΔΔ-[(phen)2Ru(tatpp)Ru(phen)2]Cl4 (ΔΔ-[4]Cl4, are a new generation of metal-based antitumor agents. These RPCs bind DNA via intercalation of the tatpp ligand, which itself is redox-active and is easily reduced at biologically relevant potentials. We have previously shown that RPC 44+ cleaves DNA when reduced by glutathione to a radical species and that this DNA cleavage is potentiated under hypoxic conditions in vitro. Here, we show that 32+ also exhibits free radical–mediated DNA cleavage in vitro and that 32+ and 44+ both exhibit selective cytotoxicity toward cultured malignant cell lines and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 32+ and 44+ (maximum tolerable doses ∼ 65 μmol/kg) is comparable with that for cisplatin (LD50 ∼ 57 μmol/kg), but unlike cisplatin, RPCs are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 32+ and 44+ are shown to suppress growth of human non–small cell lung carcinoma (∼83%), show potentiated cytotoxicity in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biologic activity suggest a promising new anticancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials. Mol Cancer Ther; 12(5); 643–53. ©2013 AACR.

Substitutionally inert complexes as chiral synthons for stereospecific supramolecular syntheses

Abstract An overview of the synthesis of diastereomerically and enantiomerically pure metallodendrimers illustrates the use of chiral, non-racemic ruthenium(II)–trisphenanthroline complexes as synthons for supramolecular synthesis. Derivitization of the substitutionally inert Δ and Λ enantiomers of [Ru(phen) 3 ] 2+ with coupling functions along the ligand periphery permits the construction of multimetallic assemblies without disturbing the stereochemistry at the chiral metal center. Specifically, 1,10-phenanthroline-5,6-dione and 1,10-phenanthroline-5,6-diamine are used because they retain the C 2 symmetry of the metal complex along the metal–bidentate ligand axis. The ring-forming condensation reaction between these two ligands leads to a symmetric, rigid, and planar tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′,3′′j]phenazine (tpphz) bridge between stereocenters. This strategy has been demonstrated previously with the stereospecific syntheses of three isomeric Ru dimers and four isomeric tetramers. Selective oxidation of these smaller oligonuclear structures (dimers and tetramers) results in the formation of peripheral dione functions at the 5 and 6 positions of the phenanthroline which is required for next generation dendrimer growth. Reactions of these new core molecules with [Ru(phen) 2 (diamine)] 2+ yields the dendritic hexanuclear, [((phen) 2 Ru(tpphz)) 2 Ru(tpphz)Ru((tpphz)(Ru(phen) 2 ) 2 ] 20+ ( Ru 6 ), and decanuclear, [(((phen) 2 Ru(tpphz)) 2 Ru(tpphz)) 3 Ru] 20+ ( Ru 10 ), dendrimers, some of which have been prepared in enantiopure form.

Global Chirality in Rigid Decametallic Ruthenium Dendrimers

Metallodendrimers with ten chiral Ru centers have been prepared in a stereospecific fashion (see picture; *=chiral Ru(diimine)(3) center). These molecules are conformationally rigid and exhibit well-defined global topologies: some diastereomers exhibit macroscopically chiral structures, others show a disklike topology. This difference in global or tertiary structure is exemplified by differences in their colloidal behavior, as observed in electric birefringence measurements.

Enantiomeric separation of chiral ruthenium(II) complexes using capillary electrophoresis.

Capillary zone electrophoresis (CZE) and micellar capillary electrophoresis (MCE) were applied for the enantiomeric separation of nine mononuclear tris(diimine)ruthenium(II) complexes as well as the separation of all stereoisomers of a dinuclear tris(diimine)ruthenium(II) complex. Nine cyclodextrin (CD) based chiral selectors were examined as run buffer additives to evaluate their effectiveness in the enantiomeric separation of tris(diimine)ruthenium(II) complexes. Seven showed enantioselectivity. Sulfated gamma-cyclodextrin (SGC), with four baseline and three partial separations, was found to be the most useful chiral selector. In CZE mode, the derivatized gamma-CDs were more effective than beta-CDs while sulfated CDs work better than carboxymethyl CDs. In MCE mode, hydroxypropyl beta-CD separated the greatest number of tris(diimine) ruthenium(II) complexes. The effects of chiral selector concentration, run buffer pH and concentration, the concentration ratio between chiral selector and other factors were investigated.

Driving Multi-electron Reactions with Photons: Dinuclear Ruthenium Complexes Capable of Stepwise and Concerted Multi-electron Reduction

Using biological precedents, it is expected that concerted, multi-electron reduction processes will play a significant role in the development of efficient artificial photosynthetic systems. We have found that the dinuclear ruthenium complexes [(phen)2Ru(tatpp)Ru(phen)2]4+ (P) and [(phen)2Ru(tatpq) Ru(phen)2]4+ (Q) undergo photodriven 2- and 4-electron reductions, respectively, in the presence of a sacrificial reductant. Importantly, these processes are completely reversible upon exposure to air, and consequently, these complexes have the potential to be used catalytically in multi-electron transfer reactions. A localized molecular orbital description of the ligands and complexes is used to explain both the function and spectroscopy of these complexes. In both complexes, the reducing equivalents are stored in the π* orbitals of the bridging ligands and depending on the solution pH, various protonation states of the reduced species of P and Q are obtained. Under basic conditions, the photochemical pathway favors sequential single-electron reductions, while neutral or slightly acidic conditions give rise to proton-coupled multi-electron transfer. In fact, at sufficiently acidic pH, only a coupled two-electron, 2-proton process is seen. Few molecular photocatalysts are capable of proton-coupled multi-electron transfer, which is believed to be a fundamental component of light-activated energy storage in nature.

Solar photothermochemical alkane reverse combustion.

Significance An efficient solar process for the one-step conversion of CO2 and H2O to C5+ liquid hydrocarbons and O2 would revolutionize how solar fuel replacements for gasoline, jet, and diesel solar fuels could be produced and could lead to a carbon-neutral fuel cycle. We demonstrate that this reaction is possible in a single-step process by operating the photocatalytic reaction at elevated temperatures and pressures. The process uses cheap and earth-abundant catalytic materials, and the unusual operating conditions expand the range of materials that can be developed as photocatalysts. Whereas the efficiency of the current system is not commercially viable, it is far from optimized and it opens a promising new path by which such solar processes may be realized. A one-step, gas-phase photothermocatalytic process for the synthesis of hydrocarbons, including liquid alkanes, aromatics, and oxygenates, with carbon numbers (Cn) up to C13, from CO2 and water is demonstrated in a flow photoreactor operating at elevated temperatures (180–200 °C) and pressures (1–6 bar) using a 5% cobalt on TiO2 catalyst and under UV irradiation. A parametric study of temperature, pressure, and partial pressure ratio revealed that temperatures in excess of 160 °C are needed to obtain the higher Cn products in quantity and that the product distribution shifts toward higher Cn products with increasing pressure. In the best run so far, over 13% by mass of the products were C5+ hydrocarbons and some of these, i.e., octane, are drop-in replacements for existing liquid hydrocarbons fuels. Dioxygen was detected in yields ranging between 64% and 150%. In principle, this tandem photochemical–thermochemical process, fitted with a photocatalyst better matched to the solar spectrum, could provide a cheap and direct method to produce liquid hydrocarbons from CO2 and water via a solar process which uses concentrated sunlight for both photochemical excitation to generate high-energy intermediates and heat to drive important thermochemical carbon-chain-forming reactions.

Retention of optical activity during conversion of Λ-[Ru(1,10-phenanthroline)3]2+ to Λ-[Ru(1,10-phenanthroline-5,6-dione)3]2+ and Λ-[Ru(dipyrido[a:3,2-h:2′,3′-c-]-phenazine)3]2+

Complete retention of stereochemistry about the metal center is observed during the oxidation of Λ-[Ru(phen)3]2+ in sulfuric acid–nitric acid–bromide mixture to Λ-[Ru(phendione)3]2+ (Λ-1) and subsequent conversion to Λ-[Ru(dppz)3]2+ (Λ-2) (where dppz=dipyrido[a:3,2-h:2′,3′-c-]-phenazine) as determined by NMR in the presence of Eu((+)tfc)3 in CD2Cl2. The solubility of the complex cations in the CD2Cl2 is increased dramatically by prior addition of the chiral lanthanide shift reagent which increases the overall sensitivity of the test. Under these conditions, the optical purities of doped samples of chiral [Ru(phen)3]Cl2 containing 5% of the minor enantiomer could be determined to within 2% by integration. However, samples doped with 3% of the minor isomer did not show a discernable minor isomer peak — establishing the limits of the test. Also reported is an improved synthesis of 1 which consistently gives pure product in 80% yield. UV–Vis and CD data for all three complexes in H2O and acetonitrile are presented.

Hierarchical structure in assemblies of enantiopure ruthenium trisdiimine complexes: a biomimetic approach utilizing primary, secondary, tertiary and quaternary structural elements

Abstract Rigid, diastereomerically-pure and enantiomerically-pure polynuclear and dendritic assemblies of ruthenium(II)trisphenanthroline complexes show a structural complexity that mimics some of the structural hierarchy found in biological systems. Hexanuclear ( Ru 6 ) and decanuclear ( Ru 10 ) assemblies show a discernable and tunable primary, secondary and tertiary structure. Solution electric birefringence studies of colloids formed from various stereoisomers Ru 6 or Ru 10 show dramatic and distinctive differences between isomers with differing tertiary structure; indicating, in effect, that different quaternary structures (colloidal structures) are formed as a function of tertiary structure. New synthetic approaches to tune the Ru to Ru distance, to change the geometry of the core (new structural motifs) and to develop a convergent approach to even higher nuclearity dendrimers are presented.

Ligand-triplet-fueled long-lived charge separation in ruthenium(II) complexes with bithienyl-functionalized ligands.

Ruthenium(II) polypyridyl complexes with pendant bithienyl ligands exhibiting unusually long-lived (τ ~ 3-7 μs) charge-separated excited states and a large amount of stored energy (ΔG° ~ 2.0 eV) are reported. A long-lived ligand-localized triplet acts as an energy reservoir to fuel population of an interligand charge-transfer state via an intermediate metal-to-ligand charge-transfer state in these complexes.