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Dosage delivery of sensitive reagents enables glove-box-free synthesis

Abstract

Contemporary organic chemists employ a broad range of catalytic and stoichiometric methods to construct molecules for applications in the material sciences1, and as pharmaceuticals2,3,4,5, agrochemicals, and sensors6. The utility of a synthetic method may be greatly reduced if it relies on a glove box to enable the use of air- and moisture-sensitive reagents or catalysts. Furthermore, many synthetic chemistry laboratories have numerous containers of partially used reagents that have been spoiled by exposure to the ambient atmosphere. This is exceptionally wasteful from both an environmental and a cost perspective. Here we report an encapsulation method for stabilizing and storing air- and moisture-sensitive compounds. We demonstrate this approach in three contexts, by describing single-use capsules that contain all of the reagents (catalysts, ligands, and bases) necessary for the glove-box-free palladium-catalysed carbon–fluorine7,8,9, carbon–nitrogen10,11, and carbon–carbon12 bond-forming reactions. This strategy should reduce the number of error-prone, tedious and time-consuming weighing procedures required for such syntheses and should be applicable to a wide range of reagents, catalysts, and substrate combinations.

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Figure 1: Wax capsules for the glove-box-free Pd-catalysed nucleophilic fluorination of aryl triflates.
Figure 2: Wax capsules for the glove-box-free Pd-catalysed nucleophilic fluorination of aryl bromides.
Figure 3: Wax capsules for the Pd-catalysed CN cross-coupling of 1° and 2° amines with aryl halides.
Figure 4: Wax capsules for the Pd-catalysed Negishi cross-coupling of 2-pyridylzinc dioxanate.

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Acknowledgements

Research reported in this publication was supported by the National Institutes of Health under award number R01GM46059. A.C.S. thanks the National Institutes of Health for a postdoctoral fellowship (1F32GM108092-01A1). J.R.C. thanks the National Science Foundation for a pre-doctoral fellowship (1122374). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Y. Ye for providing samples of L2. We also thank M. Pirnot, Y. Wang, and C. Nguyen for assistance with the preparation of the manuscript.

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Contributions

S.L.B. had the idea to encapsulate reagents in wax; A.C.S. and H.G.L. invented the capsules and designed their preparation; A.C.S., H.G.L., and S.L.B. designed the research; A.C.S., H.G.L., and J.R.C. prepared the filled capsules; A.C.S., H.G.L., J.R.C., and A.Z. performed the experiments; A.C.S. wrote the manuscript. All authors commented on the final draft of the manuscript and contributed to the analysis and interpretation of the data.

Corresponding author

Correspondence to Stephen L. Buchwald.

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Competing interests

MIT holds patents on the ligands and precatalysts used in this paper, from which S.L.B. and former/current co-workers receive royalty payments.

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Sather, A., Lee, H., Colombe, J. et al. Dosage delivery of sensitive reagents enables glove-box-free synthesis. Nature 524, 208–211 (2015). https://doi.org/10.1038/nature14654

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