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Keeping an eye on all the players: The combination of bulky phosphonium tags and pressurized sample infusion transforms electrospray ionization mass spectrometry into a tool capable of producing dense data on the relative concentrations of all components of a catalytic reaction, such as the palladium‐catalyzed coupling of an aryl iodide with phenylacetylene (see graph).

Real-time monitoring of the Suzuki–Miyaura reaction using mass spectrometry during sequential addition of the various reaction components suggests that a dynamic series of equilibria exist in these solutions. Depending on conditions, the boronic acid can be dehydrated, deprotonated, hydroxylated (or alkoxylated), or fluorinated. Palladium–phosphine species present include Pd(0) (to which the aryl iodide rapidly oxidatively adds), the Pd­(II) aryl iodide complex, a cationic Pd­(II) species formed by dissociation of the iodide ligand, and the Pd­(II) bisaryl complex that ultimately extrudes the product through reductive elimination. No fluorinated or hydr­(alk-)­oxylated palladium complexes were observed under catalytic conditions. Several transmetalation combinations were excluded as reactive partners, but several possibilities remain, and more than one mechanism is likely to be operative, even under similar conditions.

The rate of hydrodehalogenation of aryl iodides with a palladium catalyst in methanol exhibits a strong primary kinetic isotope effect from both CD3OD and CH3OD, suggesting that deprotonation plays a major role in the mechanism.

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New triruthenium-carbonyl clusters derivatized with glucose-modified bicyclophosphite ligands have been synthesized. These compounds were found to have cytostatic and cytotoxic activity and depending on the number of bicyclophosphite ligands, and could be tuned for either anti-cancer or specific anti-angiogenic activity. While some compounds had a broad cellular toxicity profile in several cell types others showed endothelial cell specific dose-dependent anti-proliferative and anti-migratory efficacy. A profound inhibition of angiogenesis was also observed in the in vivo chicken chorioallantoic membrane (CAM) model, and consequently, these new compounds have considerable potential in drug design, e.g. for the treatment of cancer.T he development of metal-based anti-cancer compounds has traditionally focused on cytotoxic platinumbased compounds, several of which are widely applied in the clinic [1][2][3] . In recent years, however, there has been increasing interest in the development of ruthenium-based anticancer compounds that appear to operate via very different mechanisms, as compared to the clinically used platinum drugs [4][5][6] . Indeed, ruthenium complexes tend to be less cytotoxic towards cancer cells in vitro and their propensity to bind DNA is lower. Two ruthenium compounds, indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]), termed KP1019 7 , and imidazolium trans-[tetrachloro(dimethylsulfoxide)(1H-imidazole)ruthenate(III)]), termed NAMI-A 8 , are presently in phase II clinical trials, the latter compound showing both anti-metastatic and anti-angiogenic activity in preclinical models. We recently found that a very different type of ruthenium compound, organometallic ruthenium(II) complexes, [Ru(g 6 -arene)Cl 2 (PTA)] (arene 5 toluene and pcymene, PTA 5 1,3,5-triaza-7-phosphaadamantane), also exhibit anti-metastatic 9 and anti-angiogenic 10 properties. Indeed, the effect of these small molecules was at least equivalent to that of sunitinib/SutentH or sorafenib/NaxavarH, clinically used tyrosine kinase inhibitors with anti-angiogenic properties 11 . The promising activities of the ruthenium compounds dictate the need for information on their biomolecular targets and suggests a clinical relevance. In this respect a large number of ruthenium compounds have been evaluated in vitro although classical in vitro cytotoxicity screens have proven, in the past, not to be particularly informative of in vivo activity 4,12 . While most ruthenium-based compounds that have been evaluated as putative anti-cancer agents are mononuclear species with the central ruthenium ion in the 21 or 31 oxidation states, a few studies describing the in vitro activity of ruthenium(0) and osmium (0) clusters have been published 13,14 . Many of these cluster compounds contain carbon monoxide (CO) and/or other ligands, and notably, the biological importance of CO as an essential mediator of numerous effects, including anti-inflammatory-and anti-proliferative activity, has recently been reported 15 . Indeed, a number of CO rel...

Alle Mitspieler im Blick: Die Kombination aus sperrigen Phosphonium‐Gruppen als Markierung und Probeninfusion unter Druck ermöglicht es, mithilfe von Elektrosprayionisations‐Massenspektrometrie einen dichten Datensatz für die relativen Konzentrationen aller Komponenten einer katalytischen Reaktion zu erheben. Als Beispiel diente die palladiumkatalysierte Kupplung eines Aryliodids mit Phenylacetylen (siehe Diagramm).

The mechanism of the Sonogashira reaction in methanol was studied in detail using pressurized sample infusion electrospray ionization mass spectrometry (PSI-ESI-MS). Several key intermediates were identified and their structures were assigned by MS/MS studies. Cationic and anionic charged-tagged substrates were employed to look into the mechanism of this reaction from variety of angles. A reverse kinetic isotope effect was observed in which the reaction rate is accelerated in deuterated solvents (kH/kD = 0.6). The reaction was found to be zero order with respect to the aryl iodide and first order with respect to the phenylacetylene. A Hammett parameter of ρ = 1.4 indicates that the reaction is more favorable for aryl iodides with para EWGs. No evidence of product inhibition, dimerization of palladium catalyst, or agglomeration were observed. However, catalyst decomposition was inferred from a non-zero intercept in the plot of catalyst loading versus reaction rate. Monitoring the reaction by PSI-ESI-(-)MS on neutral and negatively charged substrates at variety of concentrations and conditions did not reveal any detectable anionic palladium complexes. Likewise no evidence of carbopalladation and relevant intermediates in the absence of a base was observed.