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Reaction screening in multiwell plates: high-throughput optimization of a Buchwald–Hartwig amination

Abstract

Chemical space is vast, and chemical reactions involve the complex interplay of multiple variables. As a consequence, reactions can fail for subtle reasons, necessitating screening of conditions. High-throughput experimentation (HTE) techniques enable a more comprehensive array of data to be obtained in a relatively short amount of time. Although HTE can be most efficiently achieved with automated robotic dispensing equipment, the benefits of running reaction microarrays can be accessed in any regularly equipped laboratory using inexpensive consumables. Herein, we present a cost-efficient approach to HTE, examining a Buchwald–Hartwig amination as our model reaction. Experiments are carried out in a machined aluminum 96-well plate, taking advantage of solid transfer scoops and pipettes to facilitate rapid reagent transfer. Reaction vials are simultaneously heated and mixed, using a magnetic stirrer, and worked up in parallel, using a plastic filter plate. Analysis by gas chromatography provides the chemist with 96 data points with minimal commitment of time and resources. The best-performing experiment can be selected for scale-up and isolation, or the data can be used for designing future optimization experiments.

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Fig. 1: Advantages of a high-throughput approach to optimizing reaction conditions.
Fig. 2
Fig. 3: Equipment used within this protocol.
Fig. 4
Fig. 5: Preparation for high-throughput experimentation.
Fig. 6: Essential equipment for high-throughput reaction setup.
Fig. 7: Layout for dosing the 96-well plate in a high-throughput evaluation of the Buchwald–Hartwig amination.
Fig. 8: Assembly of a 96-well plate for high-throughput experimentation.
Fig. 9: Equipment used during the analysis preparation of a high-throughput experiment.
Fig. 10: Depicting the results obtained from this protocol.

Data availability

The authors declare that all the data supporting the findings of this study are available within the article and in the Supplementary Information files. All the data analysis was performed using published tools and packages and has been provided with the paper.

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Acknowledgements

Financial support for this work was provided by the University of Ottawa, the National Science and Engineering Research Council of Canada (NSERC), and the Canada Research Chair program. We thank the Canadian Foundation for Innovation (CFI) and the Ontario Ministry of Research, Innovation, & Science for essential infrastructure.

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Authors

Contributions

A.C., R.C. and S.G.N. designed the experiments. A.C. performed the experiments. A.C., R.C. and S.G.N. wrote the manuscript.

Corresponding author

Correspondence to Stephen G. Newman.

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The authors declare no competing interests.

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Peer review information Nature Protocols thanks Frank Glorius and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Key reference using this protocol

Kashani, S. K., Jessiman, J. E. & Newman, S. G. Org. Process Res. Dev. 24, 1948–1954 (2020): https://doi.org/10.1021/acs.oprd.0c00018

Supplementary information

Supplementary Information

Supplementary Procedure, Results, Figs. 1–18, Table 1 and Blueprints.

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Cook, A., Clément, R. & Newman, S.G. Reaction screening in multiwell plates: high-throughput optimization of a Buchwald–Hartwig amination. Nat Protoc 16, 1152–1169 (2021). https://doi.org/10.1038/s41596-020-00452-7

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