Mechanistic features of the copper-free Sonogashira reaction from ESI-MS

Abstract

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.

Mechanism of copper-free Sonogashira reaction operates through palladium-palladium transmetallation

“…It should be noted that the appearance of the induction period in the Cu-free Sonogashira reaction strongly depends on the reaction conditions, and can easily remain unnoticed. Nevertheless, it is apparent from some previous mechanistic studies where the reactions were intentionally made sluggish for the monitoring purposes 29 .…”

Organische Reaktionen in Mikrotröpfchen: Analyse von Reaktionsbeschleunigungen durch Massenspektrometrie

“…Anschließend werden wir uns mit dem Rätsel befassen, mit dem der Kurzaufsatz begann, und danach Anwendungen für die neuartige Technik der Reaktionsbeschleunigung in begrenztem Volumen vorstellen. Da es gute Übersichtsartikel zur Reaktionsverfolgung mittels Massenspektrometrie gibt, darunter von Eberlin und Mitarbeitern zur Untersuchung von Reaktionen wie der Stille‐Reaktion, der Baylis‐Hillman‐Reaktion und der Biginelli‐Reaktion mittels ESI, von De Angelis zur Untersuchung der Ugi‐Reaktion und der Ugi‐Smiles‐Reaktion unter Anwendung der ESI sowie von Metzger und McIndoe zur Untersuchung von metallkatalysierten Reaktionen mittels ESI, außerdem von Zare und Mitarbeitern zur Anwendung der DESI zur Erforschung von metallorganischen Reaktionen oder zum Abfangen von kurzlebigen Zwischenprodukten, wird dieser Aspekt nicht behandelt. Stattdessen geben wir einen Überblick zu in Tröpfchen verfolgten beschleunigten Reaktionen und diskutieren mögliche Mechanismen.…”

Mechanistic Study of Pd/NHC‐Catalyzed Sonogashira Reaction: Discovery of NHC‐Ethynyl Coupling Process

“…Due to ionic nature of proposed intermediates and catalyst evolution product, mass spectrometry offers the best capabilities to solve mechanistic problems as electrospray ionization is a soft ionization technique. In such a case, utilization of ESI‐MS, [24, 36] CID, [37–38] and IRMPD [39–41] is the best choice to get an insight into the system.…”