High-throughput screening of organic reactions in microdroplets using desorption electrospray ionization mass spectrometry (DESI-MS): hardware and software implementation

Abstract

<p>Implementation of a novel method for high-throughput screening of reactions in microdroplets. The reaction and analysis steps are performed simultaneously using desorption electrospray ionization mass spectrometry (DESI-MS) at a rate of up to 1 reaction mixture per second.</p>

Automated High-Throughput System Combining Small-Scale Synthesis with Bioassays and Reaction Screening

“…The main output of these screening experiments is typically a yes/no answer to the question of whether or not a specific reaction generates an expected product under certain conditions, allowing for optimization of synthetic conditions and providing a starting point for scale-up. 6,7,63,70,71 Typically, no quantitative data are sought through organic reaction screening, although MS information can be readily utilized to assess compound purity.…”

“…The system has been successfully used to study multiple organic reactions through HTS campaigns. The reactions include N-alkylation, 70 N -acylation, 71 Sonogashira coupling, 12 nitrosation, 9 Suzuki cross-coupling, 63,72 aromatic nucleophilic substitution (S N Ar), 7 aldol reaction, 73 and reductive amination. 6 Capabilities have also been demonstrated for studies of enzymatic systems, such as acetylcholinesterase, which include the determination of Michaelis–Menten kinetic parameters, as well as the screening and characterization of both inhibitors and reactivators.…”

Glass surface as strong base, ‘green’ heterogeneous catalyst and degradation reagent

“…First, we used the high-throughput system which is capable of screening thousands of reaction conditions per day [16][17][18] to test how various base-catalyzed chemical reactions, including elimination, solvolysis, imine formation, Katritzky reaction and Knoevenagel condensation, are affected by addition of glass microspheres. Methanol was added to containers containing glass microspheres (diameter: 32.5 µm, 0.02 equivalents) and then reactant solutions in methanol were added in stoichiometric amounts to reach a final concentration of 1 mM.…”

“…[7][8][9][10][11][12] Recently, glass beads have been used to deliver nanomoles of solid reagents in highthroughput reaction screening 13 but, to our best knowledge, there has been no report on studying glass-catalyzed chemical reactions systematically using any high-throughput screening (HTS) system. In this study we use a desorption electrospray ionization mass spectrometry (DESI-MS) 14,15 based high-throughput system 16 with hardware and software features that enable reproducible quantitative data to be generated from minimal amounts (50 nL) of sample solution. The integrated automatic platform allows both synthetic reactions 17 and enzymatic reactions 18 to be studied at a throughput of 1 s per sample.…”

High‐Throughput Label‐Free Enzymatic Assays Using Desorption Electrospray‐Ionization Mass Spectrometry

“…nucleophilic aromatic substitution, nitrosation, N ‐alkylation, Suzuki cross‐coupling) have been explored using this system, showing its capabilities for reaction screening and ng scale synthesis in microdroplets [20–22, 33, 34] . Extensive hardware and software developments have been implemented to allow reproducible and robust operation of the integrated (fluidics‐analysis‐data) platform, which operates with sample amounts in the low ng range and analysis times less than 1 s per spot [35] . Adding the ability to perform HT enzymatic bioassays to this DESI‐based HT system is a significant step towards consolidating a platform capable of in situ screening, synthesis and bioanalysis, all leveraged by the same analytical technique, a simple automated workflow, and complete integration of all components.…”