Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Unveiling the impact of the light source and steric factors on [2 + 2] heterocycloaddition reactions

Nature Synthesis volume 2, pages 26–36 (2023)Cite this article

Subjects

Abstract

Information gained from in-depth mechanistic investigations can be used to control the selectivity of reactions, leading to expansion of the generality of synthetic processes and discovery of new reactivity. Here, we investigate the mechanism of light-driven [2 + 2] heterocycloadditions (Paternò–Büchi reactions) between indoles and ketones to develop insight into these processes. Using ground-state ultraviolet–visible absorption and transient absorption spectroscopy, together with density functional theory calculations, we found that the reactions can proceed via an exciplex or electron–donor–acceptor complex, which are key intermediates in determining the stereoselectivity of the reactions. We used this discovery to control the diastereoselectivity of the reactions, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the electron–donor–acceptor complex is increasingly favoured, and the diastereomeric ratio (d.r.) of the product moves from >99:<1 to 47:53. In contrast, switching from methyl to ipropyl substitution favours the exciplex intermediate, reversing the d.r. from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of photoreactions, creating mechanistic pathways to previously inaccessible stereochemical variants.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The [2 + 2] heterocycloaddition process.
Fig. 2: Spectroscopic studies of the PB reaction and identification of three different possible pathways.
Fig. 3: Computational insights into the exciplex and EDA complex manifolds.
Fig. 4: Diastereodivergent pathways with benzil.
Fig. 5: Diastereodivergent pathways with α-ketoesters.
Fig. 6: Using steric parameters to gain control over diastereoselection.
Fig. 7: Generality of the developed light-driven process and in-flow implementation.

Similar content being viewed by others

Data availability

All relevant data supporting the findings of this study, including experimental procedures and compound characterization, NMR spectra and other spectroscopic analysis are available within the article and its Supplementary Information.

References

  1. Yoon, T. P., Ischay, M. A. & Du, J. Visible light photocatalysis as a greener approach to photochemical synthesis. Nat. Chem. 2, 527–532 (2010).

    Article  CAS  Google Scholar 

  2. Minisci, F. et al. Additions and corrections – Polar effects in free-radical reactions selectivity and reversibility in the homolytic benzylation of protonated heteroaromatic bases. J. Org. Chem. 51, 4326 (1986).

    Article  Google Scholar 

  3. Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).

    Article  CAS  Google Scholar 

  4. Mateos, J. et al. A visible-light Paternò-Büchi dearomatisation process towards the construction of oxeto-indolinic polycycles. Chem. Sci. 11, 6532–6538 (2020).

    Article  CAS  Google Scholar 

  5. Franceschi, P., Mateos, J., Vega‐Peñaloza, A. & Dell’Amico, L. Microfluidic visible‐light Paternò–Büchi reaction of oxindole enol ethers. Eur. J. Org. Chem. 2020, 6718–6722 (2020).

  6. Zheng, J., Dong, X. & Yoon, T. P. Divergent photocatalytic reactions of α-ketoesters under triplet sensitization and Photoredox conditions. Org. Lett. 22, 6520–6525 (2020).

    Article  CAS  Google Scholar 

  7. Paternò, E. & Chieffi, G. Sintesi in Chimica Organica per Mezzo Della Luce. Nota II. Composti Degli Idrocarburi Non Saturi Con Aldeidi e Chetoni. Gazz. Chim. Ital. 39, 341 (1909).

    Google Scholar 

  8. Büchi, G., Inman, C. G. & Lipinsky, E. S. Light-catalyzed organic reactions. I. The reaction of carbonyl compounds with 2-methyl-2-butene in the presence of ultraviolet light. J. Am. Chem. Soc. 76, 4327–4331 (1954).

    Article  Google Scholar 

  9. Bull, J. A., Croft, R. A., Davis, O. A., Doran, R. & Morgan, K. F. Oxetanes: recent advances in synthesis, reactivity, and medicinal chemistry. Chem. Rev. 116, 12150–12233 (2016).

    Article  CAS  Google Scholar 

  10. Turro, N. J. et al. Molecular photochemistry of alkanones in solution: α-cleavage, hydrogen abstraction, cycloaddition, and sensitization reactions. Acc. Chem. Res. 5, 92–101 (1972).

    Article  CAS  Google Scholar 

  11. Mattay, J., Gersdorf, J. & Buchkremer, K. Photoreactions of biacetyl with electron‐rich olefins. An extended mechanism. Chem. Ber. 120, 307–318 (1987).

    Article  CAS  Google Scholar 

  12. Fréneau, M. & Hoffmann, N. The Paternò-Büchi reaction—mechanisms and application to organic synthesis. J. Photochem. Photobiol. C Photochem. Rev. 33, 83–108 (2017).

    Article  Google Scholar 

  13. Mateos, J., Cuadros, S., Vega-Peñaloza, A. & Dell’Amico, L. Unlocking the synthetic potential of light-excited aryl ketones: applications in direct photochemistry and photoredox catalysis. Synlett 33, 116–128 (2022).

    Article  CAS  Google Scholar 

  14. Salem, L. Surface crossings and surface touchings in photochemistry. J. Am. Chem. Soc. 96, 3486–3501 (1974).

    Article  CAS  Google Scholar 

  15. Griesbeck, A. G., Abe, M. & Bondock, S. Selectivity control in electron spin inversion processes: regio- and stereochemistry of Paternò-Büchi photocycloadditions as a powerful tool for mapping intersystem crossing processes. Acc. Chem. Res. 37, 919–928 (2004).

    Article  CAS  Google Scholar 

  16. Crisenza, G. E. M., Mazzarella, D. & Melchiorre, P. Synthetic methods driven by the photoactivity of electron donor-acceptor complexes. J. Am. Chem. Soc. 142, 5461–5476 (2020).

    Article  CAS  Google Scholar 

  17. Matsumura, K., Mori, T. & Inoue, Y. Wavelength control of diastereodifferentiating Paternó-Büchi reaction of chiral cyanobenzoates with diphenylethene through direct versus charge-transfer excitation. J. Am. Chem. Soc. 131, 17076–17077 (2009).

    Article  CAS  Google Scholar 

  18. Sun, D., Hubig, S. M. & Kochi, J. K. Oxetanes from [2+2] cycloaddition of stilbenes to quinone via photoinduced electron transfer. J. Org. Chem. 64, 2250–2258 (1999).

    Article  CAS  Google Scholar 

  19. Zhang, Y., Xue, J., Gao, Y., Fun, H. K. & Xu, J. H. Photoinduced [2+2] cycloadditions (the Paterno–Büchi reaction) of 1-acetylisatin with enol ethers—regioselectivity, diastereoselectivity and acid catalysed transformations of the spirooxetane products. J. Chem. Soc. Perkin Trans. 1 2, 345–353 (2002).

    Article  Google Scholar 

  20. Kandukuri, S. R. et al. X-ray characterization of an electron donor-acceptor complex that drives the photochemical alkylation of indoles. Angew. Chemie Int. Ed. 54, 1485–1489 (2015).

    Article  CAS  Google Scholar 

  21. Buzzetti, L., Crisenza, G. E. M. & Melchiorre, P. Mechanistic studies in photocatalysis. Angew. Chemie Int. Ed. 58, 3730–3747 (2019).

    Article  CAS  Google Scholar 

  22. Freilich, S. C. & Peters, K. S. Observation of the 1,4-biradical in the Paterno-Buchi reaction. J. Am. Chem. Soc. 103, 6255–6257 (1981).

    Article  CAS  Google Scholar 

  23. Rehm, D. & Weller, A. Kinetics of fluorescence quenching by electron and H‐atom transfer. Isr. J. Chem. 8, 259–271 (1970).

    Article  CAS  Google Scholar 

  24. Mattay, J., Runsink, J., Rumbach, T., Ly, C. & Gersdorf, J. Selectivity and charge transfer in photoreactions of α, α, α-trifluorotoluene with olefins. J. Am. Chem. Soc. 107, 2557–2558 (1985).

    Article  CAS  Google Scholar 

  25. Li, H.-F., Cao, W., Ma, X., Xie, X., Xia, Y. & Ouyang, Z. Visible-Light-Driven [2 + 2] Photocycloadditions between Benzophenone and C═C Bonds in Unsaturated Lipids. J. Am. Chem. Soc. 142, 3499–3505 (2020).

    Article  CAS  Google Scholar 

  26. Mieres-Perez, J., Costa, P., Mendez-Vega, E., Crespo-Otero, R. & Sander, W. Switching the spin state of pentafluorophenylnitrene: isolation of a singlet arylnitrene complex. J. Am. Chem. Soc. 140, 17271–17277 (2018).

    Article  CAS  Google Scholar 

  27. Gutiérrez-Hernández, A. et al. Deep eutectic solvent choline chloride/ p-toluenesulfonic acid and water favor the enthalpy-driven binding of arylamines to maleimide in Aza-Michael addition. J. Org. Chem. 86, 223–234 (2021).

    Article  Google Scholar 

  28. Mori, T. & Inoue, Y. Charge-transfer excitation: unconventional yet practical means for controlling stereoselectivity in asymmetric photoreactions. Chem. Soc. Rev. 42, 8122–8133 (2013).

    Article  CAS  Google Scholar 

  29. Trost, B. M., Dong, G. & Vance, J. A. Cyclic 1,2-diketones as core building blocks: a strategy for the total synthesis of (−)-terpestacin. Chemistry 16, 6265–6277 (2010).

    Article  CAS  Google Scholar 

  30. Samanta, S., Roy, D., Khamarui, S. & Maiti, D. K. Ni(ii)-salt catalyzed activation of primary amine-sp3Cα-H and cyclization with 1,2-diketone to tetrasubstituted imidazoles. Chem. Commun. 50, 2477–2480 (2014).

    Article  CAS  Google Scholar 

  31. Matsumura, K., Mori, T. & Inoue, Y. Solvent and temperature effects on diastereodifferentiating Paternó-Büchi reaction of chiral alkyl cyanobenzoates with diphenylethene upon direct versus charge-transfer excitation. J. Org. Chem. 75, 5461–5469 (2010).

    Article  CAS  Google Scholar 

  32. Saito, H., Mori, T., Wada, T. & Inoue, Y. Diastereoselective [2 + 2] photocycloaddition of stilbene to chiral fumarate. Direct versus charge-transfer excitation. J. Am. Chem. Soc. 126, 1900–1906 (2004).

    Article  CAS  Google Scholar 

  33. Aoki, Y., Matsuki, N., Mori, T., Ikeda, H. & Inoue, Y. Exciplex ensemble modulated by excitation mode in intramolecular charge-transfer dyad: effects of temperature, solvent polarity, and wavelength on photochemistry and photophysics of tethered naphthalene-dicyanoethene system. Org. Lett. 16, 4888–4891 (2014).

    Article  CAS  Google Scholar 

  34. Nagasaki, K., Inoue, Y. & Mori, T. Entropy-driven diastereoselectivity improvement in the Paternò–Büchi reaction of 1-naphthyl aryl ethenes with a chiral cyanobenzoate through remote alkylation. Angew. Chemie Int. Ed. 57, 4880–4885 (2018).

    Article  CAS  Google Scholar 

  35. D’Auria, M. The Paternò-Büchi reaction – a comprehensive review. Photochem. Photobiolog. Sci. 18, 2297–2362 (2019).

    Article  Google Scholar 

  36. Griesbeck, A. G., Buhr, S., Fiege, M., Schmickler, H. & Lex, J. Stereoselectivity of triplet photocycloadditions: 1 diene-carbonyl reactions and solvent effects. J. Org. Chem. 63, 3847–3854 (1998).

    Article  CAS  Google Scholar 

  37. Harris, C. B., Ippen, E. P., Mourou, G. & Zewail A. H. Ultrafast Phenomena VIII (Springer, 1993).

  38. Ikeda, N., Koshioka, M., Masuhara, H. & Yoshihara, K. Picosecond dynamics of excited singlet states in organic microcrystals: diffuse reflectance laser photolysis study. Chem. Phys. Lett. 150, 452–456 (1988).

    Article  CAS  Google Scholar 

  39. Singh, A. K., Palit, D. K. & Mittal, J. P. Conformational relaxation dynamics in the excited electronic states of benzil in solution. Chem. Phys. Lett. 360, 443–452 (2002).

    Article  CAS  Google Scholar 

  40. Fang, T. S. & Singer, L. A. Variable temperature studies on the luminescence from benzil in a polymethylmethacrylate glass. An example of matrix controlled photorotamerism. Chem. Phys. Lett. 60, 117–121 (1978).

    Article  CAS  Google Scholar 

  41. Charton, M. Steric effects. I. Esterification and acid-catalyzed hydrolysis of esters. J. Am. Chem. Soc. 97, 1552–1556 (1975).

    Article  CAS  Google Scholar 

  42. Harper, K. C., Bess, E. N. & Sigman, M. S. Multidimensional steric parameters in the analysis of asymmetric catalytic reactions. Nat. Chem. 4, 366–374 (2012).

    Article  CAS  Google Scholar 

  43. Sigman, M. S. & Miller, J. J. Examination of the role of taft-type steric parameters in asymmetric catalysis. J. Org. Chem. 74, 7633–7643 (2009).

    Article  CAS  Google Scholar 

  44. Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V. & Noël, T. Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016).

    Article  Google Scholar 

  45. Mateos, J. et al. A microfluidic photoreactor enables 2-methylbenzophenone light-driven reactions with superior performance. Chem. Commun. 54, 6820–6823 (2018).

    Article  CAS  Google Scholar 

  46. Chapman, S. J. et al. Cooperative stereoinduction in asymmetric photocatalysis. J. Am. Chem. Soc. 144, 4206–4213 (2022).

    Article  CAS  Google Scholar 

  47. Poplata, S., Tröster, A., Zou, Y.-Q. & Bach, T. Recent advances in the synthesis of cyclobutanes by olefin [2+2] photocycloaddition reactions. Chem. Rev. 116, 9748–9815 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge P. Franceschi, P. Andreetta and G. Simionato (Department of Chemical Sciences, University of Padova) for preliminary experiments, and S. Bonacchi (Department of Chemical Sciences, University of Padova) for insightful discussions. This project was supported by Ministero dell’Università (MUR) (grant No. PRIN 2020927WY3_002 to L.D.), the European Union, European Research Concilium (ERC) (starting grant No. SYNPHOCAT 101040025 to L.D.), Cariparo, project Synergy within the call Ricerca Scientifica d’Eccellenza 2018 (to L.D.), University of Padova (to P.C.), Seal of Excellence@UNIPD (to P.C.) and QuantaCOF (to P.C.).

Author information

Authors and Affiliations

  1. Department of Chemical Sciences, University of Padova, Padova, Italy

    Javier Mateos, Francesco Rigodanza, Paolo Costa, Alberto Vega-Peñaloza, Elisa Fresch, Elisabetta Collini, Marcella Bonchio, Andrea Sartorel & Luca Dell’Amico

  2. Dipartimento di Scienze Chimiche e Farmaceutiche, University of Ferrara, Ferrara, Italy

    Mirco Natali

Authors
  1. Javier Mateos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Rigodanza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paolo Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mirco Natali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alberto Vega-Peñaloza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisa Fresch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elisabetta Collini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marcella Bonchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrea Sartorel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luca Dell’Amico
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.M. and L.D. wrote the manuscript with contributions from all the authors. J.M. and L.D. conceived the project and devised the experiments. J.M. and A.V.-P. carried out the reactions and isolated and characterized the products. J.M., L.D., M.B. and A.S. rationalized the experimental results. F.R., M.N., E.C. and E.F. performed the spectroscopic investigations using TAS. P.C. and A.S. performed the DFT calculations.

Corresponding author

Correspondence to Luca Dell’Amico.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Axel Griesbeck, Norbert Hoffmann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Experimental details and DFT calculations, Supplementary sections A–M, and Supplementary Figs. S.A.1–S.K.17.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mateos, J., Rigodanza, F., Costa, P. et al. Unveiling the impact of the light source and steric factors on [2 + 2] heterocycloaddition reactions. Nat. Synth 2, 26–36 (2023). https://doi.org/10.1038/s44160-022-00191-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-022-00191-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing