Powerful insight into catalytic mechanisms through simultaneous monitoring of reactants, products, and intermediates.

Electrospray ionization mass spectrometry (ESIMS) has become a valuable tool in the mechanistic study of organometallic catalytic reactions. Analysis is fast, intermediates at low concentrations can be detected, and complexmixtures are tractable. The family of palladium-catalyzed C C bondforming reactions are the most studied by ESIMS. Although the majority of these investigations have focused on the structural identification of short-lived or low-concentration intermediates, some recent studies have monitored the intensities of intermediates or reactants and products over time. However, no one has yet shown this technique to be capable of providing robust kinetic information for reactants, products, by-products, and low-abundance intermediates simultaneously and under standard reaction conditions. We show herein how powerful this information can be in leading reaction design. The copper-free Sonogashira (Heck alkynylation) reaction is widely used in the synthesis of natural products, pharmaceuticals, and novel materials, but the mechanism is not well understood. Ideally, the reaction should be observed under typical reaction conditions for meaningful information to be obtained about the mechanism, because under such conditions anions and bases as well as alkynes are thought to act as ligands for palladium, with complex effects on the reaction efficiency. In most cases, a large excess of an amine base is required to promote reaction; however, the exact role of the base is in question. Dieck and Heck and Amatore et al. suggested a carbopalladation mechanism in which the terminal alkyne undergoes carbopalladation and the base consumes the H formed during the b-hydride elimination that forms the product. Ljundahl et al. prefer a deprotonation mechanism in which deprotonation of the terminal alkyne by the amine occurs from the cationic intermediate [Pd(Ar)(PR3)(NR’3)(HC CR’’)] or the neutral intermediate [Pd(Ar)(PR3)(X)(HC CR’’)], depending on the electronic nature of the alkyne. An anionic mechanism has also been proposed in which [Pd(PR3)2X] and [Pd(PR3)(X)(Ar)(CCR’’)] intermediates feature. The identity of palladium-containing intermediates has been proposed on the basis of electrochemical or NMR spectroscopic data but not through direct observation. Charged tags are required for the detection of species otherwise invisible to ESIMS, an idea first introduced by Adlhart and Chen; we used an aryl iodide functionalized with a phosphonium hexafluorophosphate salt, [p-IC6H4CH2PPh3] [PF6] . This tag provides very low detection limits owing to its high surface activity, and the noncoordinating counterion reduces ion pairing. The bulky nature of the charged group ensures that the ionization efficiency is largely insensitive to the remaining structure of the ion, so the intensity of the various ions correspond very closely to their real concentration (see the Supporting Information). ESIMS data on reaction progress collected under typical reaction conditions by using pressurized sample infusion (PSI) compare well with H NMR and UV/Vis spectroscopic data (Figure 1). The number of data points is much higher for