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A Perspective on the Analytical Challenges Encountered in High-Throughput Experimentation

Cite this: Org. Process Res. Dev. 2021, 25, 3, 354–364
Publication Date (Web):January 20, 2021
https://doi.org/10.1021/acs.oprd.0c00463
Copyright © 2021 American Chemical Society
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Abstract

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High-throughput experimentation (HTE) is a well-established technique used in the pharmaceutical industry to accelerate compound synthesis and route optimization through automated chemical processes. A key part of any HTE workflow is the analytical component, through which the reaction outcome can be determined. The development of new analytical techniques capable of high-throughput data generation from nanoscale chemical reactions has been required to streamline the HTE process and address challenges generated through the recent move to miniaturize synthesis. In this Perspective, we review the currently available state-of-the-art analytical methods, discuss the challenges encountered in high-throughput analysis—with a particular focus on the analysis of nanoscale reactions, and provide a future outlook on potential developments in the field.

It is worth noting that the level of spectral information obtainable through LC–MS analysis is in part dictated by the mass analyzer(s) employed. For relatively little expense, a single-quadrupole instrument is sufficient to quantify a limited number of ions, while an ion trap may provide structural information through fragmentation, although quantitative power will be limited. High-resolution MS analyzers such as time-of-flight (TOF) can predict the empirical formulas of unknown compounds, while tandem mass spectrometers, such as quadrupole time-of-flight (Q-TOF) excel at overall sensitivity, albeit at a much higher price point.

In relation to experimental information disclosed in Table 1 and Figure 9, MISER acquisition LC–MS experiments were performed on an Agilent 1290 Infinity II system. The Agilent stack comprised a G7120A binary pump, a G7167B multisampler, a G7116B column compartment, a G7117B diode array detector, and a G6135B quadrupole LC–MS detector with multimode (simultaneous ESI and APCI) ionization in the positive mode. The system was controlled by OpenLab Chemstation Edition software with the FIA mode enabled. Separations were carried out on a 2.0 mm i.d. × 30 mm length, 1.9 μm YMC-Triart C18 column by isocratic elution at a flow rate of 1.5 mL/min. The LC eluents were 16% solvent A (0.1% formic acid in H2O) and 84% solvent B (acetonitrile). The column was maintained at a temperature of 40 °C. The MISERgrams were obtained from continuous sample injections (0.5 μL) every 13 s. The positive ion multimode parameters were as follows: fragmentor, 60 V; drying gas flow, 12 L/min; nebulizer pressure, 35 psig; drying gas temperature, 350 °C; vaporizer temperature, 250 °C; capillary voltage, 3000 V; corona current, 1 μA; charging voltage, 2000 V.

Cited By


This article is cited by 6 publications.

  1. Laura Buglioni, Fabian Raymenants, Aidan Slattery, Stefan D. A. Zondag, Timothy Noël. Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry. Chemical Reviews 2022, 122 (2) , 2752-2906. https://doi.org/10.1021/acs.chemrev.1c00332
  2. Alfie G. Wills, Sylvain Charvet, Claudio Battilocchio, Christopher C. Scarborough, Katherine M. P. Wheelhouse, Darren L. Poole, Nessa Carson, Julien C. Vantourout. High-Throughput Electrochemistry: State of the Art, Challenges, and Perspective. Organic Process Research & Development 2021, 25 (12) , 2587-2600. https://doi.org/10.1021/acs.oprd.1c00167
  3. Chang Liu. Acoustic Ejection Mass Spectrometry: Fundamentals and Applications in High-Throughput Drug Discovery. Expert Opinion on Drug Discovery 2022, 11 https://doi.org/10.1080/17460441.2022.2084069
  4. Robbert van Putten, Natalie S. Eyke, Lorenz M. Baumgartner, Victor L. Schultz, Georgy A. Filonenko, Klavs F. Jensen, Evgeny Alexandrovich Pidko. Automation and microfluidics for the efficient, fast, and focused reaction development of asymmetric hydrogenation catalysis. ChemSusChem 2022, https://doi.org/10.1002/cssc.202200333
  5. Zachery Crandall, Kevin Basemann, Long Qi, Theresa L. Windus. Rxn Rover: automation of chemical reactions with user-friendly, modular software. Reaction Chemistry & Engineering 2022, 7 (2) , 416-428. https://doi.org/10.1039/D1RE00265A
  6. Melodie Christensen, Lars P. E. Yunker, Parisa Shiri, Tara Zepel, Paloma L. Prieto, Shad Grunert, Finn Bork, Jason E. Hein. Automation isn't automatic. Chemical Science 2021, 12 (47) , 15473-15490. https://doi.org/10.1039/D1SC04588A

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