Spatial and temporal control of the alkyne–azide cycloaddition by photoinitiated Cu(II) reduction

Journal name:
Nature Chemistry
Volume:
3,
Pages:
256–259
Year published:
DOI:
doi:10.1038/nchem.980
Received
Accepted
Published online

Abstract

The click reaction paradigm is focused on the development and implementation of reactions that are simple to perform while being robust and providing exquisite control of the reaction and its products. Arguably the most prolific and powerful of these reactions, the copper-catalysed alkyne–azide reaction (CuAAC) is highly efficient and ubiquitous in an ever increasing number of synthetic methodologies and applications, including bioconjugation, labelling, surface functionalization, dendrimer synthesis, polymer synthesis and polymer modification. Unfortunately, as the Cu(I) catalyst is typically generated by the chemical reduction of Cu(II) to Cu(I), or added as a Cu(I) salt, temporal and spatial control of the CuAAC reaction is not readily achieved. Here, we demonstrate catalysis of the CuAAC reaction via the photochemical reduction of Cu(II) to Cu(I), affording comprehensive spatial and temporal control of the CuAAC reaction using standard photolithographic techniques. Results reveal the diverse capability of this technique in small molecule synthesis, patterned material fabrication and patterned chemical modification.

At a glance

Figures

  1. General scheme for a photocatalysed CuAAC reaction.
    Figure 1: General scheme for a photocatalysed CuAAC reaction.

    a, A photoinitiator is first used to generate radicals, which reduce Cu(II) to Cu(I). The transiently generated Cu(I) then catalyses the 1,3-dipolar cycloaddition. The Cu(I) is ultimately either reduced to copper metal or disproportionates to form Cu(0) and Cu(II). Reactions of Cu(I) and oxygen are also possible (not shown). b, 1-Hexyne (1), ethyl azidoacetate (2), and Irgacure 819 (3) were used in the 1H-NMR and FTIR experiments, and a 3K PEG-dialkyne (4), a 10K PEG-tetraazide (5) and Irgacure 2959 (6) were used for hydrogel synthesis.

  2. Photo-CuAAC reaction kinetics.
    Figure 2: Photo-CuAAC reaction kinetics.

    Complete conversion of the azide species to form triazole 7 is shown to occur in ~60 min for a dimethylformamide solution with 200 mM 1-hexyne (1), 200 mM ethyl azidoacetate (2), 10 mM copper sulfate and 10 mM Irgacure 819 (3) irradiated with 10 mW cm−2 400–500 nm light. Also shown is the azide conversion for mixtures lacking Cu(II), irradiation or photoinitiator. No significant reaction is noted for any of these control samples and all three lines overlie one another. Conversion is also shown when irradiation was ceased after 5 or 10 min during the course of the reaction.

  3. Hydrogel formation patterned by photo-CuAAC reaction.
    Figure 3: Hydrogel formation patterned by photo-CuAAC reaction.

    a, Hydrogels are formed by irradiating a 3K PEG dialkyne (4) and a 10K PEG tetraazide (5) in the presence of Irgacure 2959 (6) and copper sulfate using masked light. The gels form only in the irradiated area. b, Bright-field image showing one such dehydrated gel, ~4 µm thick. The photomask consists of 25, 50, 100, 200, 300 and 400 µm bars separated by 100 µm spaces.

  4. Fluorescent patterning of a hydrogel by the photo-CuAAC reaction.
    Figure 4: Fluorescent patterning of a hydrogel by the photo-CuAAC reaction.

    a, In situ patterning of a hydrogel (photograph) was achieved by first forming an alkyne-rich gel via the thiol-yne click reaction of a 10K tetrathiol and 3K dialkyne. A solution of photoinitiator, copper sulfate and an azide-labelled fluorophore was swollen into the gel. Irradiation with a photomask (same as in Fig. 3) resulted in the generation of Cu(I) in the irradiated areas and the subsequent pCuAAC reaction between the pendant alkyne groups and azide-functionalized fluorophore. b, After removal of unreacted fluorophore, wide-field microscopy reveals the pattern of the fluorophore.

Compounds

5 compounds View all compounds
  1. 1-Hexyne
    Compound 1 1-Hexyne
  2. Ethyl 2-azidoacetate
    Compound 2 Ethyl 2-azidoacetate
  3. (Phenylphosphoryl)bis(mesitylmethanone)
    Compound 3 (Phenylphosphoryl)bis(mesitylmethanone)
  4. 2-Hydroxy-1-(4-(2-hydroxyethoxy)phenyl)-2-methylpropan-1-one
    Compound 6 2-Hydroxy-1-(4-(2-hydroxyethoxy)phenyl)-2-methylpropan-1-one
  5. Ethyl 2-(4-butyl-1H-1,2,3-triazol-1-yl)acetate
    Compound 7 Ethyl 2-(4-butyl-1H-1,2,3-triazol-1-yl)acetate

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Author information

Affiliations

  1. Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado 80309-0424, USA

    • Brian J. Adzima,
    • Youhua Tao,
    • Christopher J. Kloxin,
    • Cole A. DeForest,
    • Kristi S. Anseth &
    • Christopher N. Bowman
  2. Howard Hughes Medical Institute, University of Colorado, UCB Box 424 Boulder, Colorado 80309-0424, USA

    • Kristi S. Anseth

Contributions

C.N.B., C.J.K. and B.J.A. developed the concept. B.J.A., Y.T., C.J.K., C.A.D., K.S.A. and C.N.B. designed the experiments. C.A.D. synthesized the materials used. B.J.A., Y.T. and C.A.D. performed the experiments. B.J.A., C.J.K., K.S.A. and C.N.B. composed the manuscript.

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The authors declare no competing financial interests.

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