Luminescent Iridium(III) Cyclometalated Complexes with 1,2,3-Triazole “Click” Ligands

A series of cyclometalated iridium­(III) complexes with either 4-(2-pyridyl)-1,2,3-triazole or 1-(2-picolyl)-1,2,3-triazole ancillary ligands to give complexes with either 5- or 6-membered chelate rings were synthesized and characterized by a combination of X-ray crystallography, electron spin ionization–high-resolution mass spectroscopy (ESI-HRMS), and nuclear magnetic resonance (NMR) spectroscopy. The electronic properties of the complexes were probed using absorption and emission spectroscopy, as well as cyclic voltammetry. The relative stability of the complexes formed from each ligand class was measured, and their excited-state properties were compared. The emissive properties are, with the exception of complexes that contain a nitroaromatic substituent, insensitive to functionalization of the ancillary pyridyl-1,2,3-triazole ligand but tuning of the emission maxima was possible by modification of the cyclometalating ligands. It is possible to prepare a wide range of optimally substituted pyridyl-1,2,3-triazoles using copper Cu­(I)-catalyzed azide alkyne cycloaddition, which is a commonly used “click” reaction, and this family of ligands represent an useful alternative to bipyridine ligands for the preparation of luminescent iridium­(III) complexes

Direct versus Water-Mediated Protodecarboxylation of Acetic Acid Catalyzed by Group 10 Carboxylates, [(phen)M(O₂CCH₃)]⁺

The gas-phase protodecarboxylation of acetic acid catalyzed by group 10 metal complexes was examined using a combination of multistage mass spectrometry experiments in an ion trap mass spectrometer, DFT calculations, and theoretical kinetic modeling. Two related catalytic cycles sharing two common intermediates were examined. The entry points to both cycles are the metal acetate complexes [(phen)­M­(O₂CCH₃)]⁺ (where phen = 1,10-phenanthroline), which were formed via direct electrospray ionization of solutions of the complexes [(phen)­M­(O₂CCH₃)₂] in water. Step 1 of both cycles involves decarboxylation of [(phen)­M­(O₂CCH₃)]⁺ under collision-induced dissociation (CID) conditions to form the organometallic species [(phen)­M­(CH₃)]⁺. The ease of decarboxylation follows the order Pd > Pt > Ni as determined via energy-resolved CID experiments, which is in agreement with the activation energies for decarboxylation estimated from DFT calculations. Step 2 of cycle 1 involves an ion–molecule reaction between [(phen)­M­(CH₃)]⁺ and acetic acid to close the cycle by regenerating the metal acetate complex [(phen)­M­(O₂CCH₃)]⁺. DFT calculations reveal that an acid–base acetolysis mechanism is favored over an oxidative addition/reductive elimination mechanism proceeding via the M­(IV) intermediate [(phen)­M­(CH₃)­(H)­(O₂CCH₃)]⁺. In contrast, step 2 of cycle 2 involves [(phen)­M­(CH₃)]⁺ reacting with water to form the hydroxide [(phen)­M­(OH)]⁺, which subsequently reacts with acetic acid in step 3 to re-form [(phen)­M­(O₂CCH₃)]⁺ and water, thereby completing the catalytic cycle. Experiment and theory reveal that cycle 2 operates only for M = Ni

Copper and Silver Complexes of Tris(triazole)amine and Tris(benzimidazole)amine Ligands: Evidence that Catalysis of an Azide–Alkyne Cycloaddition (“Click”) Reaction by a Silver Tris(triazole)amine Complex Arises from Copper Impurities

The synthesis and characterization of a silver complex of the tripodal triazole ligand, tris­(benzyltriazolylmethyl)­amine (TBTA, <b>L</b>^<b>1</b>), that is used as promoter to enhance Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC) reactions is reported. X-ray analysis of the silver­(I) complex with <b>L</b>¹ reveals a dinuclear cation, [Ag₂(<b>L</b>^<b>1</b>)₂]²⁺, that is essentially isostructural to the copper­(I) analogue. While the [Ag₂(<b>L</b>^<b>1</b>)₂]­(BF₄)₂ complex provides catalysis for the azide–alkyne cycloaddition process, evidence is presented that this arises from trace copper contamination. The synthesis of silver­(I), copper­(II), and copper­(I) complexes of a second tripodal ligand, tris­(2-benzimidazolymethyl)­amine (<b>L</b>^<b>2</b>), which is used to enhance the rate of CuAAC reactions, is also reported. X-ray crystallography of the Cu^I complex [Cu^I₃(<b>L</b>^<b>2</b>)₂(CH₃CN)₂]­(BF₄)₃ offers structural insight into previous mechanistic speculation about the role of this ligand in the CuAAC reaction

Role of the Metal, Ligand, and Alkyl/Aryl Group in the Hydrolysis Reactions of Group 10 Organometallic Cations [(L)M(R)]⁺

The reactions of water with the coordinatively unsaturated group 10 organometallic cations [(L)­M­(R)]⁺ (<b>4</b>; where L = 1,10-phenanthroline (phen), neocuproine (neo); M = nickel, palladium, platinum; R = CH₃, C₆H₅, CH₂C₆H₅), formed via decarboxylation of the carboxylate complexes [(L)­M­(O₂CR)]⁺, were examined in the gas phase using a combination of multistage mass spectrometry experiments and DFT calculations at the M06/SDD6-31+G­(d) level of theory. Two main types of primary product ions were observed: the aqua adduct [(L)­M­(R)­(H₂O)]⁺ (<b>5</b>) and the hydroxide [(L)­M­(OH)]⁺ (<b>7</b>), formed via a hydrolysis reaction. A secondary product ion, arising from formation of the adduct [(L)­M­(OH)­(H₂O)]⁺, was also observed when L = phen, R = CH₃, and M = Pt. The rates of reaction of <b>4</b> and the product branching ratios for <b>5</b> and <b>7</b> were dependent upon the nature of M, L, and R. When L = phen and R = CH₃, the hydroxide <b>7</b> dominates for Ni, with the adduct <b>5</b> as the major product for both Pd and Pt. For R = C₆H₅ the rate of the reaction is slower, while for R = CH₂C₆H₅ no reaction occurs. Replacing the phen auxiliary ligand with neo dramatically slows down the rate of reaction with water. DFT calculations reveal that an acid–base hydrolysis mechanism is favored over an oxidative addition/reductive elimination mechanism proceeding via the M­(IV) intermediate [(L)­M­(CH₃)­(H)­(OH)]⁺. Furthermore, the relative energies calculated for the barriers of these hydrolysis reactions are consistent with the experimentally observed reactivity trends. This mechanism is also supported by RRKM theory/master equation simulations, which demonstrate that formation of the aqua adduct and hydroxide can be explained by competition between unimolecular dissociation and collisional deactivation of the chemically activated reaction adduct within the ion trap. The lack of reactivity of the benzyl systems appears to arise from η^<i>3</i> binding of the benzyl group, which blocks access to the incoming water. Finally, links are made to group 10 three-coordinate organometallic complexes in the condensed phase

A Click Chemistry Approach to 5,5′-Disubstituted-3,3′-Bisisoxazoles from Dichloroglyoxime and Alkynes: Luminescent Organometallic Iridium and Rhenium Bisisoxazole Complexes

5,5′-Disubstituted-3,3′-bisisoxazoles are prepared in one step by the dropwise addition of aqueous potassium hydrogen carbonate to a mixture of dichloroglyoxime and terminal alkynes. The reaction exhibits a striking preference for the 5,5′-disubstituted 3,3′-bisisoxazole over the 4,5′-regioisomer. Organometallic iridium and rhenium bisisoxazole complexes are luminescent with emission wavelengths varying depending upon the identity of the 5,5′-substituent (phenyl, butyl)

Comparison of ⁶⁴Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and <i>in Vitro</i>/<i>in Vivo</i> Stability

High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, <i>in vitro</i> stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with ⁶⁴Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (<i>p</i>-SCN-Bn-DOTA, <i>p</i>-SCN-Bn-Oxo-DO3A, <i>p</i>-SCN-NOTA, and <i>p</i>-SCN-PCTA), three DTPA derivatives (<i>p</i>-SCN-Bn-DTPA, <i>p</i>-SCN-CHX-A″-DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO₂H) = (1-NH₂-8-NHCO­(CH₂)₃CO₂H)­sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]­icosane). Radiolabeling efficiency under various conditions, <i>in vitro</i> stability in serum at 37 °C, and <i>in vivo</i> biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO₂H were conjugated to rituximab by thiourea bond formation with an average of 4.9 ± 0.9 chelators per antibody molecule. Sar-CO₂H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody molecule. Efficiencies of ⁶⁴Cu radiolabeling were dependent on the concentration of immunoconjugate. Notably, the ⁶⁴Cu-NOTA-rituximab conjugate demonstrated the highest radiochemical yield (95%) under very dilute conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, containing 1/10th the number of chelators per antibody compared to that of other conjugates, retained high labeling efficiency (98%) at an antibody concentration of 250 nM. In contrast to the radioimmunoconjugates containing DTPA derivatives, which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6% dissociation of ⁶⁴Cu over 48 h. <i>In vivo</i> biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. While all the macrocyclic bifunctional chelators are suitable for molecular imaging using ⁶⁴Cu-labeled antibody conjugates, NOTA and sar-CO₂H show significant advantages over the others in that they can be radiolabeled rapidly at room temperature, under dilute conditions, resulting in high specific activity

Synthesis, Structural Characterization, and Gas-Phase Unimolecular Reactivity of Bis(diphenylphosphino)amino Copper Hydride Nanoclusters [Cu₃(X)(μ₃‑H)((PPh₂)₂NH)₃](BF₄), Where X = μ₂‑Cl and μ₃‑BH₄

An electrospray ionization mass spectrometry (ESI-MS) survey of the types of cationic copper clusters formed from an acetonitrile solution containing a 1:1:20 mixture of tetrakis­(acetonitrile)­copper­(I) tetrafluoroborate [Cu­(MeCN)₄(BF₄)], bis­(diphenylphosphino)­amine (dppa = (Ph₂P)₂NH = L), and NaBH₄ revealed a major peak, which based on both the accurate masses and isotope distribution was assigned as [Cu₃(BH₄)­(H)­(L)₃]⁺. This prompted synthetic efforts resulting in isolation of the dppa ligated trinuclear copper hydride nanoclusters, [Cu₃(μ₂-Cl)­(μ₃-H)­(L)₃]­(BF₄) and [Cu₃(μ₃-BH₄)­(μ₃-H)­(L)₃]­(BF₄), which were subsequently structurally characterized using high resolution ESI-MS, X-ray crystallography, NMR, and IR spectroscopy. The X-ray structures reveal a common structural feature of the cation, in which the three copper­(I) ions adopt a planar trinuclear Cu₃ geometry coordinated on the bottom face by a μ₃-hydride and surrounded by three dppa ligands. ESI-MS of [Cu₃(<i>μ</i>₂-Cl)­(μ₃-H)­(L)₃]­(BF₄) and [Cu₃(μ₃-BH₄)­(μ₃-H)­(L)₃]­(BF₄) produces [Cu₃(μ₂-Cl)­(μ₃-H)­(L)₃]⁺ and [Cu₃(μ₃-BH₄)­(μ₃-H)­(L)₃]⁺. The unimolecular gas-phase ion chemistry of these cations was examined under multistage tandem mass spectrometry conditions using collision-induced dissociation (CID). CID of both cations proceeds via ligand loss to give [Cu₃(μ₃-H)­(X)­(L)₂]⁺, which is in competition with BH₃ loss in the case of X = BH₄. DFT calculations on the fragmentation of [Cu₃(μ₃-BH₄)­(μ₃-H)­(L^Me)₃]⁺ suggest that BH₃ loss produces the hitherto elusive [Cu₃(μ₃-H)­(μ₂<i>-</i>H)­(L^Me)₃]⁺, which undergoes further fragmentation via H₂ loss. CID of the deuterium labeled cluster [Cu₃(μ₃-D)­(μ₃-BD₄)­(L)₃]⁺ reveals that the competing losses of ligand and BD₃ yield [Cu₃(μ₃-BD₄)­(μ₃-D)­(L)₂]⁺ and [Cu₃(D)₂(L)₃]⁺ as primary products, which subsequently fragment via further losses of BD₃ or a ligand to give [Cu₃(D)₂(L)₂]⁺. The coordinated hydrides in the latter ion are activated toward elimination of D₂ to give [Cu₃(L)₂]⁺. Loss of HD and 2HD are minor channels, consistent with higher DFT predicted endothermicities to form [Cu₃(D)­(L)­(L-H)]⁺ and [Cu₃(L-H)₂]⁺

Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK

This research aimed to develop new tumor targeted theranostic agents taking advantage of the similarities in coordination chemistry between technetium and rhenium. A γ-emitting radioactive isotope of technetium is commonly used in diagnostic imaging, and there are two β^– emitting radioactive isotopes of rhenium that have the potential to be of use in radiotherapy. Variants of the 6-hydrazinonicotinamide (HYNIC) bifunctional ligands have been prepared by appending thioamide functional groups to 6-hydrazinonicotinamide to form pyridylthiosemicarbazide ligands (SHYNIC). The new bidentate ligands were conjugated to the tumor targeting peptides Tyr³-octreotate and cyclic-RGD. The new ligands and conjugates were used to prepare well-defined {MO}³⁺ complexes (where M = ^99mTc or ^natRe or ¹⁸⁸Re) that feature two targeting peptides attached to the single metal ion. These new SHYNIC ligands are capable of forming well-defined rhenium and technetium complexes and offer the possibility of using the ^99mTc imaging and ^188/186Re therapeutic matched pairs

A Click Chemistry Approach to 5,5′-Disubstituted-3,3′-Bisisoxazoles from Dichloroglyoxime and Alkynes: Luminescent Organometallic Iridium and Rhenium Bisisoxazole Complexes

5,5′-Disubstituted-3,3′-bisisoxazoles are prepared in one step by the dropwise addition of aqueous potassium hydrogen carbonate to a mixture of dichloroglyoxime and terminal alkynes. The reaction exhibits a striking preference for the 5,5′-disubstituted 3,3′-bisisoxazole over the 4,5′-regioisomer. Organometallic iridium and rhenium bisisoxazole complexes are luminescent with emission wavelengths varying depending upon the identity of the 5,5′-substituent (phenyl, butyl)