7412 Chem. Commun., 2010, 46, 7412–7414 This journal is c The Royal Society of Chemistry 2010 Direct observation of key intermediates by negative-ion electrospray ionisation mass spectrometry in palladium-catalysed cross-couplingw Krista L. Vikse, a Matthew A. Henderson, a Allen G. Oliver b and J. Scott McIndoe* a Received 23rd July 2010, Accepted 19th August 2010 DOI: 10.1039/c0cc02773a Negative-ion electrospray ionisation mass spectrometry with an anionic phosphine ligand enables detection of key intermediates in the Sonogashira reaction. MS/MS techniques are used to generate a Hammett plot for the key reductive elimination step. Electrospray ionisation mass spectrometry (ESI-MS) 1 has great potential for exploring catalytic reactions, being fast, ultra-sensitive, and able to cope with complex mixtures. 2 Any ionic catalysts and their derivatives are abundant in the mass spectrum, while neutral reactants, solvents and products are absent. Palladium-catalysed cross-coupling reactions 3 have been analysed by ESI-MS since 1994, 4 and further reports have emerged regularly. 5 All have involved the positive-ion mode, and ionisation of the metal complexes of interest has proceeded through ‘‘sporting methods’’, for example loss of a halide ligand to produce [M  X] + ions, or oxidation to form [M] + radical cations. The latter is due to the fact that for every excess positive ion created in the ESI process, something must be oxidised at the charged capillary. 6 Often, this is oxidation of iron from the stainless steel capillary, but it can also be solvent or analyte; so Pd(0), being easily oxidised itself, loses an electron and forms the corresponding Pd(I) complex. And herein lies the difficulty with positive-ion ESI-MS analysis of low oxidation state electron rich metal complexes: whatever the reactivity of Pd(I) (little is known of this unusual oxidation state), it is unlikely to be the same as that of Pd(0). Similarly, [M  X] + ions are unlikely to react in the same fashion as the M precursor. Accordingly, we turned our attention to the negative ion mode. Pd(0) is easy to oxidise but hard to reduce, so a negative charge was attached to the metal complex via a charged ligand, 7 a derivative of the water-soluble mono- sulfonated triphenylphosphine, [Na][PPh 2 (m-C 6 H 4 SO 3 )]  ([Na][1]). By replacing Na + with [(Ph 3 P) 2 N] + (PPN) through salt metathesis, [PPN][1] is soluble in organic solvents and suitable for ESI-MS.z A dichloromethane solution of equimolar amounts of Pd(PPh 3 ) 4 and [PPN][1] provides a negative-ion ESI mass spectrum consisting of just [Pd(1)(PPh 3 ) n ]  (n = 1, 2). Bis(phosphino)palladium compounds are thought to be the key intermediates in a huge range of cross-coupling reactions, 8 and Fig. 1 represents the first direct MS observation of such a species unaltered by oxidation or ligand dissociation. Reactivity with trace O 2 can be eliminated by performing all reaction handling in an adjacent glovebox. 9 Formation of unsaturated Pd(PR 3 ) 2 followed by oxidative addition are widely considered to be the first steps in Pd-catalysed cross-coupling reactions involving aryl halides. 10 We chose to study the copper-free Sonogashira reaction, the coupling of an aryl halide (Ar–X) with a terminal alkyne (RC 2 H). 11 Addition of phenyl iodide to the solution resulted in immediate and complete consumption of all Pd(0) species and formation of the expected Pd(II) complex [Pd(1)(PPh 3 )(Ph)(I)]  , the first intermediate in the catalytic cycle. When subjected to MS/MS analysis, this ion decomposes exclusively by phosphine dissociation (of either 1 or PPh 3 , see ESIw). Addition of phenylacetylene and NEt 3 to the mixture containing catalytic amounts of [Pd(1)(PPh 3 )(Ar)(I)]  resulted in the formation of another intermediate, [Pd(1)(PPh 3 )- (Ar)(C 2 Ph)]  (Fig. 2). Fig. 1 Negative-ion ESI-MS of Pd(PPh 3 ) 4 + [PPN][1] in CH 2 Cl 2 . Insets: isotope pattern matching for [Pd(PPh 3 ) n (1)]  (n = 1 and 2). Fig. 2 Negative-ion ESI-MS of Pd(PPh 3 ) 4 + [PPN][1] + 100  (PhI + PhC 2 H + NEt 3 ) in CH 2 Cl 2 . Inset: isotope pattern match for [Pd(1)(PPh 3 )(Ph)(C 2 Ph)]  . a Department of Chemistry, University of Victoria, P.O. Box 3065, Victoria, BC V8W3V6, Canada. E-mail: mcindoe@uvic.ca; Fax: +1 250 721-7147; Tel: +1 250 721-7181 b Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA w Electronic supplementary information (ESI) available: Experimental details, X-ray crystal structure of [PPN][1], additional ESI-MS and ESI-MS/MS. CCDC 785943. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0cc02773a COMMUNICATION www.rsc.org/chemcomm | ChemComm Downloaded by University of Victoria on 03 May 2011 Published on 07 September 2010 on http://pubs.rsc.org | doi:10.1039/C0CC02773A View Online