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Label-assisted mass spectrometry for the acceleration of reaction discovery and optimization

Nature Chemistry volume 5, pages 423427 (2013) | Download Citation

Abstract

The identification of new reactions expands our knowledge of chemical reactivity and enables new synthetic applications. Accelerating the pace of this discovery process remains challenging. We describe a highly effective and simple platform for screening a large number of potential chemical reactions in order to discover and optimize previously unknown catalytic transformations, thereby revealing new chemical reactivity. Our strategy is based on labelling one of the reactants with a polyaromatic chemical tag, which selectively undergoes a photoionization/desorption process upon laser irradiation, without the assistance of an external matrix, and enables rapid mass spectrometric detection of any products originating from such labelled reactants in complex reaction mixtures without any chromatographic separation. This method was successfully used for high-throughput discovery and subsequent optimization of two previously unknown benzannulation reactions.

  • Compound C20H18O

    4-(Pyren-1-yl)butan-1-ol

  • Compound C40H37NO4

    (S)-4-(Pyren-1-yl)butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoate

  • Compound C30H36OSi

    Triisopropyl((5-(pyren-1-yl)pent-1-yn-1-yl)oxy)silane

  • Compound C35H40O3Si

    3-(3-(Pyren-1-yl)propyl)-2-((triisopropylsilyl)oxy)benzoic acid

  • Compound C39H43NO2Si

    (E)-3-(3-(Pyren-1-yl)propyl)-2-((triisopropylsilyl)oxy)-1-naphthaldehyde oxime

  • Compound C22H30AuF6NPSb

    (Acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoroantimonate

  • Compound C11H14O3

    3-Butyl-2-hydroxybenzoic acid

  • Compound C16H16O3

    2-Hydroxy-3-(3-phenylpropyl)benzoic acid

  • Compound C18H18O5

    2-Hydroxy-5-(methoxycarbonyl)-3-(3-phenylpropyl)benzoic acid

  • Compound C13H16O5

    3-Butyl-2-hydroxy-5-(methoxycarbonyl)benzoic acid

  • Compound C17H18O3

    4-Butyl-3-hydroxy-[1,1'-biphenyl]-2-carboxylic acid

  • Compound C11H13ClO3

    3-Butyl-6-chloro-2-hydroxybenzoic acid

  • Compound C13H9ClO3

    4-Chloro-2-hydroxy-[1,1'-biphenyl]-3-carboxylic acid

  • Compound C13H15ClO3

    6-Chloro-3-cyclohexyl-2-hydroxybenzoic acid

  • Compound C16H15ClO3

    6-Chloro-2-hydroxy-3-(3-phenylpropyl)benzoic acid

  • Compound C18H29ClO4Si

    6-Chloro-2-hydroxy-3-(2-((triisopropylsilyl)oxy)ethyl)benzoic acid

  • Compound C10H9ClO3

    6-Chloro-3-cyclopropyl-2-hydroxybenzoic acid

  • Compound C11H13ClO3

    3-(tert-Butyl)-6-chloro-2-hydroxybenzoic acid

  • Compound C15H17NO2

    (E)-3-Butyl-2-hydroxy-1-naphthaldehyde oxime

  • Compound C14H13NO2

    (E)-3-Cyclopropyl-2-hydroxy-1-naphthaldehyde oxime

  • Compound C17H19NO2

    (E)-3-Cyclohexyl-2-hydroxy-1-naphthaldehyde oxime

  • Compound C15H17NO2

    (E)-3-(tert-Butyl)-2-hydroxy-1-naphthaldehyde oxime

  • Compound C16H19NO2

    (E)-1-(3-Butyl-2-hydroxynaphthalen-1-yl)ethanone oxime

  • Compound C15H16BrNO2

    (E)-8-Bromo-3-butyl-2-hydroxy-1-naphthaldehyde oxime

  • Compound C15H16BrNO2

    (E)-6-Bromo-3-butyl-2-hydroxy-1-naphthaldehyde oxime

  • Compound C15H16ClNO2

    (E)-3-Butyl-8-chloro-2-hydroxy-1-naphthaldehyde oxime

  • Compound C17H18BrNO2

    (E)-8-Bromo-3-cyclohexyl-2-hydroxy-1-naphthaldehyde oxime

  • Compound C15H15BrN2O4

    (E)-8-Bromo-3-butyl-2-hydroxy-5-nitro-1-naphthaldehyde oxime

  • Compound C15H16BrNO2

    (E)-8-Bromo-3-(tert-butyl)-2-hydroxy-1-naphthaldehyde oxime

  • Compound C17H12BrNO2

    (E)-8-Bromo-2-hydroxy-3-phenyl-1-naphthaldehyde oxime

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Acknowledgements

This work was funded by the National Institutes of Health (P50 GM086145) and the Chicago Biomedical Consortium, with support from the Searle Funds at the Chicago Community Trust. The authors thank I. Steele for X-ray crystallographic analysis.

Author information

Affiliations

  1. Department of Chemistry (Chicago Tri-Institutional Centre for Chemical Methods and Library Development), University of Chicago, Chicago, Illinois 60637, USA

    • Jaime R. Cabrera-Pardo
    • , David I. Chai
    • , Song Liu
    •  & Sergey A. Kozmin
  2. Department of Chemistry (Chicago Tri-Institutional Centre for Chemical Methods and Library Development), Northwestern University, Evanston, Illinois 60208, USA

    • Milan Mrksich

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Contributions

J.R.C.-P. developed the reaction-screening platform, and performed and analysed all reactions using MS. D.I.C and S.L. carried out the reaction optimization and scope studies. M.M. provided assistance with instrumentation and data analysis. S.A.K. provided overall management of the project. The manuscript was written by S.A.K., M.M., J.R.C.-P. and D.I.C.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sergey A. Kozmin.

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Crystallographic information files

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    Supplementary information

    Crystallographic data for compound 10a

  2. 2.

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    Crystallographic data for compound 10e

  3. 3.

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    Crystallographic data for compound 13a

  4. 4.

    Supplementary information

    Crystallographic data for compound 13f

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DOI

https://doi.org/10.1038/nchem.1612

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