Letter | Published:

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

Nature volume 524, pages 208211 (13 August 2015) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & (eds) Nanochemistry: A Chemical Approach to Nanomaterials 2nd edn (Royal Society of Chemistry, 2009)

  2. 2.

    et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015)

  3. 3.

    et al. Multi-kilo delivery of AMG 925 featuring a Buchwald–Hartwig amination and processing with insoluble synthetic intermediates. Org. Process Res. Dev. 19, 476–485 (2015)

  4. 4.

    & Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem. Rev. 111, 2177–2250 (2011)

  5. 5.

    &. (eds) Applications of Transition Metal Catalysis in Drug Discovery and Development (Wiley, 2012)

  6. 6.

    &. (eds) Chemosensors Principles, Strategies, and Applications (Wiley, 2011)

  7. 7.

    et al. Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides. Science 325, 1661–1664 (2009)

  8. 8.

    , & An improved catalyst system for the Pd-catalyzed fluorination of (hetero)aryl triflates. Org. Lett. 15, 5602–5605 (2013)

  9. 9.

    , & Pd-catalyzed nucleophilic fluorination of aryl bromides. J. Am. Chem. Soc. 136, 3792–3795 (2014)

  10. 10.

    , & Design and preparation of new palladium precatalysts for C–C and C–N cross-coupling reactions. Chem. Sci. 4, 916–920 (2013)

  11. 11.

    & A multiligand based Pd catalyst for C–N cross-coupling reactions. J. Am. Chem. Soc. 132, 15914–15917 (2010)

  12. 12.

    , , , & Synthesis of solid 2-pyridylzinc reagents and their application in Negishi reactions. Org. Lett. 15, 5754–5757 (2013)

  13. 13.

    & Preparation of wax beads containing a reagent for release by heating. US patent 5,413,924 (1995)

  14. 14.

    & Novel stable compositions of water and oxygen sensitive compounds and their method of preparation. US patent publ. no. 2005/0288257 A1 (2005)

  15. 15.

    et al. A new chromium-based catalyst coated with paraffin for ethylene oligomerization and the effect of chromium state on oligomerization selectivity. Appl. Catal. A 235, 33–38 (2002)

  16. 16.

    & Grubbs’ catalyst in paraffin: an air-stable preparation for alkene metathesis. J. Org. Chem. 68, 6047–6048 (2003)

  17. 17.

    & Potassium hydride in paraffin: a useful base for organic synthesis. J. Org. Chem. 71, 8973–8974 (2006)

  18. 18.

    Fluorine substituent effects (on bioactivity). J. Fluor. Chem. 109, 3–11 (2001)

  19. 19.

    , & Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem. Int. Ed. 44, 1788–1805 (2005)

  20. 20.

    , & Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007)

  21. 21.

    & Modern carbon-fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 115, 612–633 (2015)

  22. 22.

    & Aromatic fluorine compounds. I. A new method for their preparation. Ber. Dtsch. Chem. Gesell. 60, 1186–1190 (1927)

  23. 23.

    & Aromatic fluorine compounds. VII. Replacement of aromatic -Cl and -NO2 groups by -F. J. Am. Chem. Soc. 78, 6034–6037 (1956)

  24. 24.

    The organometallic fluorine chemistry of palladium and rhodium: studies toward aromatic fluorination. Acc. Chem. Res. 43, 160–171 (2010)

  25. 25.

    & Aryl-fluoride reductive elimination from Pd(II): feasibility assessment from theory and experiment. J. Am. Chem. Soc. 129, 1342–1358 (2007)

  26. 26.

    & (eds) Metal-Catalyzed Cross-Coupling Reactions 2nd edn (Wiley, 2004)

  27. 27.

    , , & Advances in the field of π-conjugated 2,2′:6′,2″-terpyridines. Chem. Soc. Rev. 40, 1459–1511 (2011)

  28. 28.

    et al. 2-Pyridyl P1′-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects. J. Med. Chem. 52, 2571–2586 (2009)

  29. 29.

    & The slow-release strategy in Suzuki–Miyaura coupling. Isr. J. Chem. 50, 664–674 (2010)

  30. 30.

    , & Academia-industry symbiosis in organic chemistry. Acc. Chem. Res. 48, 712–721 (2015)

Download references

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.

Author information

Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Aaron C. Sather
    • , Hong Geun Lee
    • , James R. Colombe
    • , Anni Zhang
    •  & Stephen L. Buchwald

Authors

  1. Search for Aaron C. Sather in:

  2. Search for Hong Geun Lee in:

  3. Search for James R. Colombe in:

  4. Search for Anni Zhang in:

  5. Search for Stephen L. Buchwald in:

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.

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.

Corresponding author

Correspondence to Stephen L. Buchwald.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text and Data, Supplementary Figures, Supplementary Tables and additional references (see Contents for more details).

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature14654

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.