Fundamental and applied studies of accelerated chemical synthesis and complex mixture analysis by ambient ionization mass spectrometry

To do mass spectrometry (MS) is to engage in the art and science of creating and manipulating ions. This dissertation concerns ions produced by spray-based methods: their formation, structure, reactivity, and applications. The invention of modern electrospray ionization (ESI) by John Fenn in 1989 has revolutionized science, enabling the analysis of large biomolecules and establishing a new branch of analytical chemistry, a fact recognized with the 2002 Nobel Prize in Chemistry. The microdroplets generated during ESI, traditionally intended to introduce analyte ions to the mass spectrometer, are at the heart of it all. In 2011, members of our laboratory discovered that reaction mixtures sprayed in microdroplets form products at dramatically accelerated rates compared to bulk conditions—orders of magnitude greater, in fact. Analysis and synthesis could no longer be thought of as separate tasks but inherently coupled. Over the past fifteen years, the mechanistic intricacies and implications of this chemistry at the interface of both organic and water microdroplets—often illuminated by mass spectrometry—has been vigorously debated. These topics are briefly summarized and considered in the first chapter of this dissertation. Much of the observed reactivity is due to interfacial chemistry, particularly the partial solvation of reagents, as here demonstrated via in situ photocatalyst preparation at the surface of vapor-dosed, acoustically levitated droplets. Given that reactants at the surface of microdroplets experience a decreased local density of solvent, normally disfavored reactions (e.g. condensation in water) can proceed at the relatively “dry” surface of droplets. This insight explains the rapid microdroplet synthesis of peptides and sugars in this dissertation, findings of great significance for prebiotic chemistry. The liquid-gas interface also primes reagents for heterogeneous reactions with gases and surfaces, as demonstrated by the lithium-mediated electrochemical synthesis of ammonia from water and atmospheric dinitrogen. Because microdroplets place synthesis and analysis (including bioanalysis such as enzyme inhibition assays) on complementary timescales, high throughput MS for drug discovery can be achieved by Purdue’s unique desorption electrospray ionization (DESI) MS system. This process, along with orthogonal microdroplet synthesis of valuable products, is discussed in several of the following chapters. Lastly, the development of electrophoresis-enhanced paper spray (EePS), a method for facile separation of mixtures during ionization, as well as two-dimensional tandem mass spectrometry (2D MS/MS), an experiment suited to post-ionization mixture analysis, are discussed in the context of environmental and biological analysis.