Tandem Iridium-Catalyzed C-H Borylation/Copper-Mediated Radiofluorination of Aromatic C-H Bonds with [18F]TBAF.

Direct C-H functionalization of (hetero)aromatic C-H bonds with iridium-catalyzed borylation followed by copper-mediated radiofluorination of the in situ generated organoboronates affords fluorine-18 labeled aromatics in high radiochemical conversions and meta-selectivities. This protocol describes the benchtop reaction assembly of the C-H borylation and radiofluorination steps, which can be utilized for the fluorine-18 labeling of densely functionalized bioactive scaffolds.

C-H radiocyanation of bioactive molecules via sequential iodination/copper-mediated cross-coupling.

This report describes a net C-H radiocyanation reaction for the transformation of electron rich (hetero)aromatic substrates into 11CN-labeled products. Electrophilic C(sp2)-H iodination of the (hetero)arene with N-iodosuccinimide is followed by Cu-mediated radiocyanation with K11CN. This sequence is applied to a variety of substrates, including the nucleobases uracil and cytosine, the amino acids tyrosine and tryptophan, and the peptide LYRAGWRAFS, which undergoes selective C-H radiocyanation at the tryptophan (W) residue.

Copper-Mediated Fluoroalkylation of Aryl Bromides and Chlorides Enabled by Directing Groups.

This report describes the reactions between N-heterocyclic carbene copper(I) fluoroalkyl complexes and aryl halides bearing ortho-directing groups. Pyridine, pyrazole, oxazoline, imine, and ester directing groups are shown to dramatically enhance the reactivity of aryl bromides and chlorides with (IPr)CuI-fluoroalkyl complexes (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; fluoroalkyl = difluoromethyl and pentafluoroethyl) to afford aryl-fluoroalkyl coupling products. This approach is leveraged to achieve the Cu-catalyzed directed fluoroalkylation of a series of aryl bromide substrates.

Strategies for the Production of [11C]LY2795050 for Clinical Use.

This report describes a comparison of four different routes for the clinical-scale radiosynthesis of the κ-opioid receptor antagonist [11C]LY2795050. Palladium-mediated radiocyanation and radiocarbonylation of an aryl iodide precursor as well as copper-mediated radiocyanation of an aryl iodide and an aryl boronate ester have been investigated. Full automation of all four methods is reported, each of which provides [11C]LY2795050 in sufficient radiochemical yield, molar activity, and radiochemical purity for clinical use. The advantages and disadvantages of each radiosynthesis method are compared and contrasted.

Copper-Mediated Radiocyanation of Unprotected Amino Acids and Peptides.

This report describes a copper-mediated radiocyanation of aryl halides that is applicable to complex molecules. This transformation tolerates an exceptionally wide range of functional groups, including unprotected amino acids. As such, it enables the site-specific introduction of [11C]CN into peptides at an iodophenylalanine residue. The use of a diamine-ligated copper(I) mediator is crucial for achieving high radiochemical yield under relatively mild conditions, thus limiting racemization and competing side reactions of other amino acid side chains. The reaction has been scaled and automated to deliver radiolabeled peptides, including analogues of adrenocorticotropic hormone 1-27 (ACTH) and nociceptin (NOP). For instance, this Cu-mediated radiocyanation was leveraged to prepare >40 mCi of [11C]cyano-NOP to evaluate biodistribution in a primate using positron emission tomography. This investigation provides preliminary evidence that nociceptin crosses the blood-brain barrier and shows uptake across all brain regions (SUV > 1 at 60 min post injection), consistent with the known distribution of NOP receptors in the rhesus brain.

Accessing Molecular Dimeric Ir Water Oxidation Catalysts from Coordination Precursors.

One ongoing challenge in the field of iridium-based water oxidation catalysts is to develop a molecular precatalyst affording well-defined homogeneous active species for catalysis. Our previous work by using organometallic precatalysts Cp*Ir(pyalk)OH and Ir(pyalk)(CO)2 (pyalk = (2-pyridyl)-2-propanolate) suggested a µ-oxo-bridged Ir dimer as the probable resting state, although the structure of the active species remained elusive. During the activation, the ligands Cp* and CO were found to oxidatively degrade into acetic acid or other products, which coordinate to Ir centers and affect the catalytic reaction. Two related dimers bearing two pyalk ligands on each iridium were crystallized for structural analysis. However, preliminary results indicated that these crystallographically characterized dimers are not active catalysts. In this work, we accessed a mixture of dinuclear iridium species from a coordination precursor, Na[Ir(pyalk)Cl4], and assayed their catalytic activity for oxygen evolution by using NaIO4 as the oxidant. This catalyst showed comparable oxygen-evolution activity to the ones previously reported from organometallic precursors without demanding oxidative activation to remove sacrificial ligands. Future research along this direction is expected to provide insights and design principles toward a well-defined active species.

Sequential Ir/Cu-Mediated Method for the Meta-Selective C-H Radiofluorination of (Hetero)Arenes.

This article describes a sequential Ir/Cu-mediated process for the meta-selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a benchtop without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/µmol (19.24 GBq/µmol) molar activity (Am), respectively.

NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides.

[18F]-labeled aryl fluorides are widely used as radiotracers for positron emission tomography (PET) imaging. Aryl halides (ArX) are particularly attractive precursors to these radiotracers, as they are readily available, inexpensive, and stable. However, to date, the direct preparation of [18F]-aryl fluorides from aryl halides remains limited to SNAr reactions between highly activated ArX substrates and K18F. This report describes an aryl halide radiofluorination reaction in which the C(sp2)-18F bond is formed via a copper-mediated pathway. Copper N-heterocyclic carbene complexes serve as mediators for this transformation, using aryl halide substrates with directing groups at the ortho position. This reaction is applied to the radiofluorination of electronically diverse aryl halide derivatives, including the bioactive molecules vismodegib and PH089.

Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging.

PURPOSE: Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C-18F bonds. This minireview examines proof-of-concept, pre-clinical, and in-human imaging studies of new and established imaging agents containing aromatic C-18F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed. METHODS: A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion. CONCLUSIONS: CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.

A Dinuclear Iridium(V,V) Oxo-Bridged Complex Characterized Using a Bulk Electrolysis Technique for Crystallizing Highly Oxidizing Compounds.

We report a general method for the preparation and crystallization of highly oxidized metal complexes that are difficult to prepare and handle by more conventional means. This method improves typical bulk electrolysis and crystallization conditions for these reactive species by substituting oxidation-prone organic electrolytes and precipitants with oxidation-resistant compounds. Specifically, we find that CsPF6 is an effective inert electrolyte in acetonitrile, and appears to have general applicability to electrochemical studies in this solvent. Likewise, CCl4 is not only an oxidation-resistant precipitant for crystallization from MeCN but it also enters the lattice. In this way, we synthesized and characterized an Ir(V,V) mono-µ-oxo dimer which only forms at a very high potential (1.9 V vs NHE). This compound, having the highest isolated oxidation state in this redox-active system, cannot be formed chemically. DFT calculations show that the oxidation is centered on the Ir-O-Ir core and facilitated by strong electron-donation from the pyalk (2-(2-pyridinyl)-2-propanolate) ligand. TD-DFT simulations of the UV-visible spectrum reveal that its royal blue color arises from electron excitations with mixed LMCT and Laporte-allowed d-d character. We have also crystallographically characterized a related monomeric Ir(V) complex, similarly prepared by oxidizing a previously reported Ir(IV) compound at 1.7 V, underscoring the general applicability of this method.

Synthesis and Characterization of Iridium(V) Coordination Complexes With an N,O-Donor Organic Ligand.

We have prepared and fully characterized two isomers of [IrIV (dpyp)2 ] (dpyp=meso-2,4-di(2-pyridinyl)-2,4-pentanediolate). These complexes can cleanly oxidize to [IrV (dpyp)2 ]+ , which to our knowledge represent the first mononuclear coordination complexes of IrV in an N,O-donor environment. One isomer has been fully characterized in the IrV state, including by X-ray crystallography, XPS, and DFT calculations, all of which confirm metal-centered oxidation. The unprecedented stability of these IrV complexes is ascribed to the exceptional donor strength of the ligands, their resistance to oxidative degradation, and the presence of four highly donor alkoxide groups in a plane, which breaks the degeneracy of the d-orbitals and favors oxidation.

Redox Activity of Oxo-Bridged Iridium Dimers in an N,O-Donor Environment: Characterization of Remarkably Stable Ir(IV,V) Complexes.

Chemical and electrochemical oxidation or reduction of our recently reported Ir(IV,IV) mono-µ-oxo dimers results in the formation of fully characterized Ir(IV,V) and Ir(III,III) complexes. The Ir(IV,V) dimers are unprecedented and exhibit remarkable stability under ambient conditions. This stability and modest reduction potential of 0.99 V vs NHE is in part attributed to complete charge delocalization across both Ir centers. Trends in crystallographic bond lengths and angles shed light on the structural changes accompanying oxidation and reduction. The similarity of these mono-µ-oxo dimers to our Ir "blue solution" water-oxidation catalyst gives insight into potential reactive intermediates of this structurally elusive catalyst. Additionally, a highly reactive material, proposed to be a Ir(V,V) µ-oxo species, is formed on electrochemical oxidation of the Ir(IV,V) complex in organic solvents at 1.9 V vs NHE. Spectroelectrochemistry shows reversible conversion between the Ir(IV,V) and proposed Ir(V,V) species without any degradation, highlighting the exceptional oxidation resistance of the 2-(2-pyridinyl)-2-propanolate (pyalk) ligand and robustness of these dimers. The Ir(III,III), Ir(IV,IV) and Ir(IV,V) redox states have been computationally studied both with DFT and multiconfigurational calculations. The calculations support the stability of these complexes and provide further insight into their electronic structures.

A Pyridine Alkoxide Chelate Ligand That Promotes Both Unusually High Oxidation States and Water-Oxidation Catalysis.

Water-oxidation catalysis is a critical bottleneck in the direct generation of solar fuels by artificial photosynthesis. Catalytic oxidation of difficult substrates such as water requires harsh conditions, so the ligand must be designed both to stabilize high oxidation states of the metal center and to strenuously resist ligand degradation. Typical ligand choices either lack sufficient electron donor power or fail to stand up to the oxidizing conditions. Our research on Ir-based water-oxidation catalysts (WOCs) has led us to identify a ligand, 2-(2'-pyridyl)-2-propanoate or "pyalk", that fulfills these requirements. Work with a family of Cp*Ir(chelate)Cl complexes had indicated that the pyalk-containing precursor gave the most robust WOC, which was still molecular in nature but lost the Cp* fragment by oxidative degradation. In trying to characterize the resulting active "blue solution" WOC, we were able to identify a diiridium(IV)-mono-µ-oxo core but were stymied by the extensive geometrical isomerism and coordinative variability. By moving to a family of monomeric complexes [IrIII/IV(pyalk)3] and [IrIII/IV(pyalk)2Cl2], we were able to better understand the original WOC and identify the special properties of the ligand. In this Account, we cover some results using the pyalk ligand and indicate the main features that make it particularly suitable as a ligand for oxidation catalysis. The alkoxide group of pyalk allows for proton-coupled electron transfer (PCET) and its strong σ- and π-donor power strongly favors attainment of exceptionally high oxidation states. The aromatic pyridine ring with its methyl-protected benzylic position provides strong binding and degradation resistance during catalytic turnover. Furthermore, the ligand has two additional benefits: broad solubility in aqueous and nonaqueous solvents and an anisotropic ligand field that enhances the geometry-dependent redox properties of its complexes. After discussion of the general properties, we highlight the specific complexes studied in more detail. In the iridium work, the isolated mononuclear complexes showed easily accessible Ir(III/IV) redox couples, in some cases with the Ir(IV) state being indefinitely stable in water. We were able to rationalize the unusual geometry-dependent redox properties of the various isomers on the basis of ligand-field effects. Even more striking was the isolation and full characterization of a stable Rh(IV) state, for which prior examples were very reactive and poorly characterized. Importantly, we were able to convert monomeric Ir complexes to [Cl(pyalk)2IrIV-O-IrIVCl(pyalk)2] derivatives that help model the "blue solution" properties and provide groundwork for rational synthesis of active, well-defined WOCs. More recent work has moved toward the study of first-row transition metal complexes. Manganese-based studies have highlighted the importance of the chelate effect for labile metals, leading to the synthesis of pincer-type pyalk derivatives. Beyond water oxidation, we believe the pyalk ligand and its derivatives will also prove useful in other oxidative transformations.

High Oxidation State Iridium Mono-µ-oxo Dimers Related to Water Oxidation Catalysis.

The highly active iridium "blue solution" chemical and electrochemical water oxidation catalyst obtained from Cp*IrL(OH) precursors (L = 2-pyridyl-2-propanoate) has been difficult to characterize as no crystal structure can be obtained because of the multiplicity of geometrical isomers present. Other data suggest complete loss of the Cp* ligand and the formation of a LIr-O-IrL unit. We have now developed a route to a series of well-defined Ir(IV,IV) mono-µ-oxo dimers, containing the closely related L2Ir-O-IrL2 unit. Unlike the catalyst, these model compounds are separable by silica gel chromatography and readily form single crystals. We report three stereoisomers with the formula ClL2Ir-O-IrL2Cl, which are fully characterized, including by X-ray crystallography, and are compared to the "blue solution". To the best of our knowledge, these species represent the first examples of structurally characterized dinuclear µ-oxo Ir(IV,IV) compounds without metal-carbon bonds.

Catalytic Oxygen Evolution from Manganese Complexes with an Oxidation-Resistant N,N,O-Donor Ligand.

There is great interest in developing Mn water-splitting catalysts due to their low cost, abundance, and relevance to the oxygen-evolving complex (OEC). Three ligands with highly donating pyridine alkoxide moieties, including 2-(pyridin-2-yl)propan-2-ol (pyalkH), 2,2'-(pyridine-2,6-diyl)bis(propan-2-ol) (py-dialkH2 ), and 2-[(2,2'-bipyridin)-6-yl]propan-2-ol (bipy-alkH), have been screened with Mn for oxygen-evolution catalysis. Complexes with the ligand bipy-alkH were shown to evolve O2 when driven by Oxone (potassium peroxymonosulfate). The catalytic mixture generated from the precursor complex [Mn(bipy-alkH)Cl2 ] retained activity in unbuffered solution beyond 160 h.

A Stable Coordination Complex of Rh(IV) in an N,O-Donor Environment.

We describe facial and meridional isomers of [Rh(III)(pyalk)3], as well as meridional [Rh(IV)(pyalk)3](+) {pyalk =2-(2-pyridyl)-2-propanoate}, the first coordination complex in an N,O-donor environment to show a clean, reversible Rh(III/IV) redox couple and to have a stable Rh(IV) form, which we characterize by EPR and UV-visible spectroscopy as well as X-ray crystallography. The unprecedented stability of the Rh(IV) species is ascribed to the exceptional donor strength of the ligands, their oxidation resistance, and the meridional coordination geometry.

Gel-assisted crystallization of [Ir4(IMe)7(CO)H10](2+) and [Ir4(IMe)8H9](3+) clusters derived from catalytic glycerol dehydrogenation.

The two title clusters were formed during iridium-catalyzed glycerol dehydrogenation and display a remarkably high NHC content. They were crystallized in either agarose or polyethylene oxide gel matrices, while more conventional crystallization techniques proved unsuccessful. Cluster [Ir4(IMe)8H9](3+), with a net charge of +3, was only crystallizable with a polyoxometalate Keggin trianion. The crystal packing of this intercluster compound is discussed. Computational studies position the iridium hydrides and provide insights into the bonding.

Selective conversion of glycerol to lactic acid with iron pincer precatalysts.

A family of iron complexes of PNP pincer ligands are active catalysts for the conversion of glycerol to lactic acid with high activity and selectivity. These complexes also catalyse transfer hydrogenation reactions using glycerol as the hydrogen source.

Methanol dehydrogenation by iridium N-heterocyclic carbene complexes.

A series of homogeneous iridium bis(N-heterocyclic carbene) catalysts are active for three transformations involving dehydrogenative methanol activation: acceptorless dehydrogenation, transfer hydrogenation, and amine monoalkylation. The acceptorless dehydrogenation reaction requires base, yielding formate and carbonate, as well as 2-3 equivalents of H2. Of the few homogeneous systems known for this reaction, our catalysts tolerate air and employ simple ligands. Transfer hydrogenation of ketones and imines from methanol is also possible. Finally, N-monomethylation of anilines occurs through a "borrowing hydrogen" reaction. Notably, this reaction is highly selective for the monomethylated product.

Efficient selective and atom economic catalytic conversion of glycerol to lactic acid.

The availability of glycerol is rapidly increasing due to the expanding biodiesel industry, which produces this polyol as the main waste material. Several value-added chemicals have been synthesized using glycerol as a feedstock; however, the conversion of glycerol to lactic acid has been investigated to a lesser extent despite the numerous and novel uses of lactic acid. We report a family of iridium complexes as the first homogeneous catalysts for the conversion of glycerol to lactic acid. These have higher activity and selectivity than the previously reported heterogeneous systems. In addition, hydrogen gas is generated as a useful byproduct. Unlike prior systems, the reactions can be performed in air, under mild conditions and without solvent. Our method has even been applied to samples of crude glycerol waste derived from the biodiesel industry without prior purification, albeit with somewhat lower activity while maintaining the same high selectivity.