A critical analysis of electrospray techniques for the determination of accelerated rates and mechanisms of chemical reactions in droplets.

Electrospray and Electrosonic Spray Ionization Mass Spectrometry (ESI-MS and ESSI-MS) have been widely used to report evidence that many chemical reactions in micro- and nano-droplets are dramatically accelerated by factors of ∼10 to 10 relative to macroscale bulk solutions. Despite electrospray's relative simplicity to both generate and detect reaction products in charged droplets using mass spectrometry, substantial complexity exists in how the electrospray process itself impacts the interpretation of the mechanism of these observed accelerated rates. ESI and ESSI are both coupled multi-phase processes, in which analytes in small charged droplets are transferred and detected as gas-phase ions with a mass spectrometer. As such, quantitative examination is needed to evaluate the impact of multiple experimental factors on the magnitude and mechanisms of reaction acceleration. These include: (1) evaporative concentration of reactants as a function of droplet size and initial concentration, (2) competition from gas-phase chemistry and reactions on experimental surfaces, (3) differences in ionization efficiency and ion transmission and (4) droplet charge. We examine (1-4) using numerical models, new ESI/ESSI-MS experimental data, and prior literature to assess the limitations of these approaches and the experimental best practices required to robustly interpret acceleration factors in micro- and nano-droplets produced by ESI and ESSI.