Practical approaches to the ESI-MS analysis of catalytic reactions Lars P.E. Yunker, Rhonda L. Stoddard and J. Scott McIndoe* Electrospray ionization mass spectrometry (ESI-MS) is a soft ionization technique commonly coupled with liquid or gas chro- matography for the identification of compounds in a one-time view of a mixture (for example, the resulting mixture generated by a synthesis). Over the past decade, Scott McIndoe and his research group at the University of Victoria have developed var- ious methodologies to enhance the ability of ESI-MS to continuously monitor catalytic reactions as they proceed. The power, sensitivity and large dynamic range of ESI-MS have allowed for the refinement of several homogenous catalytic mechanisms and could potentially be applied to a wide range of reactions (catalytic or otherwise) for the determination of their mechanis- tic pathways. In this special feature article, some of the key challenges encountered and the adaptations employed to counter them are briefly reviewed. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: mass spectrometry; catalysis; organometallic chemistry; transition metal complexes Electrospray ionization mass spectrometry (ESI-MS) is a technique that at first blush seems ideally suited to the examination of catalytic reactions. It is a fast technique which possesses great sensitivity, [1] it can cope with mixtures intractable to many other techniques [2] and it has a high dynamic range. [3] These properties are all useful for analysis of complex reaction mixtures. The sensi- tivity allows for detection of trace intermediates. Its speed – one spectrum takes a second or less to acquire – enables dense data to be collected on reactions that are over in mere minutes, but can easily be extended to reactions lasting hours. [4] Catalytic reactions are almost by necessity a soup of reactants, products, byproducts, intermediates, resting states and decomposed material; intrinsic to the property of ESI-MS is that it produces well-separated and diagnostic signals for individual components, making it capable of dissecting such mixtures. Finally, a dynamic range across several orders of magnitude enables accurate measurement of abundant and traces components alike. [5] Accordingly, ESI-MS was ear-marked as a promising technique for the analysis of catalytic reactions almost as soon as the first commercial machines appeared. The ground-breaking paper was the 1994 report by Canary, [6] detailing studying the mecha- nism of the Suzuki cross-coupling reaction. This paper introduced the idea of using a substrate that was especially amenable to the ESI-MS process, in this case a brominated pyridine. The pyridine, carrying as it did a peripheral basic site that was uninvolved in the reactivity but was easily protonated to provide [M + H] + ions, showed how the use of appropriate substrates for reactions would light up not only that species, but whatever intermediates, resting states and decomposition products that substrate was bound to. Canary used this property to take snapshots of the speciation of the reaction as it proceeded and obtained interest- ing insights into the nature of the reaction. However, despite the promising start, it is fair to say that progress has stuttered in the two decades following, with the vast majority of mechanistic studies still being conducted with other methods. The question of why ESI-MS was not a standard method for catalytic analysis was one we asked ourselves nearly ten years ago, and we’ve spent the intervening period finding out why, and developing solutions to the problems we encountered. Fortunately, we had the benefit of years of pioneering work by others, and the community has continued to inspire and innovate. This short review will, however, restrict itself to the approaches we employ to solve the problems and conclude with a short section on the information that can be obtained on catalytic reactions using these techniques. Many of the suggestions are simple precau- tions, tips and protocols which will be helpful for those looking to make better use of a technique available in most large research facilities and chemistry departments. Collectively, they can be used to enable researchers to gain insights that are beyond the capabilities of competing methods. Cross contamination Most spectroscopic methods do not need to concern themselves with what the previous user was examining. Provided the exper- iment uses clean apparatus, the only analyte being detected will be the intended one. However, ESI-MS has the notable feature that all samples pass through the same infusion system, and the sensitivity of the technique and variation in ionization response for different molecules and ions means that it is entirely plausible that an intense signal observed in a spectrum in fact originated from the previous user’s sample. Safeguarding against such cross-contamination requires certain precautions. A. Minimize shared apparatus. It is always necessary to share the capillary from which the spray emerges (and depending on instrumental design, an internal capillary designed to * Correspondence to: J. Scott McIndoe, Department of Chemistry, University of Victoria, P.O. Box 3065 Victoria, BC V8W3V6, Canada. E-mail: mcindoe@uvic.ca Department of Chemistry, University of Victoria, P.O. Box 3065, Victoria, BC, V8W3V6, Canada J. Mass Spectrom. 2014, 49,1–8 Copyright © 2014 John Wiley & Sons, Ltd. Special feature: perspective Received: 30 August 2013 Revised: 20 October 2013 Accepted: 24 October 2013 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/jms.3303 1