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Photoinduced dual bond rotation of a nitrogen-containing system realized by chalcogen substitution

Abstract

Photoinduced concerted multiple-bond rotation has been proposed in some biological systems. However, the observation of such phenomena in synthetic systems, in other words, the synthesis of molecules that undergo photoinduced multiple-bond rotation upon photoirradiation, has been a challenge in the photochemistry field. Here we describe a chalcogen-substituted benzamide system that exhibits photoinduced dual bond rotation in heteroatom-containing bonds. Introduction of the chalcogen substituent into a sterically hindered benzamide system provides sufficient kinetic stability and photosensitivity to enable the photoinduced concerted rotation. The presence of two different substituents on the phenyl ring in the thioamide derivative enables the generation of a pair of enantiomers and E/Z isomers. Using these four stereoisomers as indicators of which bonds are rotated, we monitor the photoinduced C–N/C–C concerted bond rotation in the thioamide derivative depending on external stimuli such as temperature and photoirradiation. Theoretical calculations provide insight on the mechanism of this selective photoinduced C–N/C–C concerted rotation.

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Fig. 1: Photoinduced multiple-bond rotation.
Fig. 2: Rotational barriers of C–N axis of ortho-disubstituted tertiary benzamides.
Fig. 3: Photoinduced isomerization of the chalcogen amides.
Fig. 4: Separation and stereochemical determination of each isomer.
Fig. 5: Different rotational mode of the thioamide system.
Fig. 6: Quantum chemical calculation for the reaction mechanism of the photoinduced isomerization of 8-S.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. Supplementary Data 1 contains the cartesian coordinates for the calculated structures. Source data are provided with this paper.

References

  1. Reinhard, B. & Hoffmann, W. Flexible molecules with defined shape-conformational design. Angew. Chem. Int. Ed. Engl. 31, 1124–1134 (1992).

    Article  Google Scholar 

  2. Pinheiro, P. S. M., Rodrigues, D. A., Maia, R. C., Thota, S. & Fraga, C. A. M. The use of conformational restriction in medicinal chemistry. Curr. Top. Med. Chem. 19, 1712–1733 (2019).

    Article  Google Scholar 

  3. Diaz, D. B. et al. Illuminating the dark conformational space of macrocycles using dominant rotors. Nat. Chem. 13, 218–225 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Dugave, C. & Demange, L. Cistrans isomerization of organic molecules and biomolecules: implications and applications. Chem. Rev. 103, 2475–2532 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Feringa, B. L., van Deleden, R. A., Koumura, N. & Geertsema, E. M. Chiroptical molecular switches. Chem. Rev. 100, 1789–1816 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Patel, A. B. et al. Coupling of retinal isomerization to the activation of rhodopsin. Proc. Natl Acad. Sci. USA 101, 10048–10053 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Albert, L. et al. Bistable photoswitch allows in vivo control of hematopoiesis. ACS Cent. Sci. 8, 57–66 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Yang, X. et al. Photophosphatidylserine guides natural killer cell photoimmunotherapy via Tim‑3. J. Am. Chem. Soc. 144, 3863–3874 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Scheiner, M. et al. Photoswitchable pseudoirreversible butyrylcholinesterase inhibitors allow optical control of inhibition in vitro and enable restoration of cognition in an Alzheimer’s disease mouse model upon irradiation. J. Am. Chem. Soc. 144, 3279–3284 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Zosel, F., Mercadnte, D., Nettels, D. & Schuler, B. A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction. Nat. Commun. 9, 3332 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kitzig, S., Thilemann, M., Cordes, T. & Rück-Braun, K. Light-switchable peptides with a hemithioindigo unit: peptide design, photochromism, and optical spectroscopy. ChemPhysChem 17, 1252–1263 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Yu, Z. & Hecht, S. Remote control over folding by light. Chem. Commun. 52, 6639–6653 (2016).

    Article  CAS  Google Scholar 

  13. Pianowski, Z. L. Recent implementations of molecular photoswitches into smart materials and biological systems. Chem. Eur. J. 25, 5128–5144 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Erbas-Cakmak, S., Leigh, D. A., McTernan, C. T. & Nussbaumer, A. L. Artificial molecular machines. Chem. Rev. 115, 10081–10206 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Volarić, J., Szymanski, W., Simeth, N. A. & Feringa, B. L. Molecular photoswitches in aqueous environments. Chem. Soc. Rev. 50, 12377–12449 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pooler, D. R. S., Lubbe, A. S., Crespi, S. & Feringa, B. L. Designing light-driven rotary molecular motors. Chem. Sci. 12, 14964–14986 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jeong, M. et al. Hydrazone photoswitches for structural modulation of short peptides. Chem. Eur. J. 28, e202103972 (2022).

    Article  CAS  PubMed  Google Scholar 

  18. Pesce, L., Perego, C., Grommet, A. B., Klajn, R. & Pavan, G. M. Molecular factors controlling the isomerization of azobenzenes in the cavity of a flexible coordination cage. J. Am. Chem. Soc. 142, 9792–9802 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu, R. S. H. & Asato, A. E. The primary process of vision and the structure of bathorhodopsin: a mechanism for photoisomerization of polyenes. Proc. Natl Acad. Sci. USA 82, 259–263 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu, R. S. H. Photoisomerization by Hula-Twist: a fundamental supramolecular photochemical reaction. Acc. Chem. Res. 34, 555–562 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Luis, M. F., Tadeusz, A., Santoro, F., Ferré, N. & Massimo, O. Tracking the excited-state time evolution of the visual pigment with multiconfigurational quantum chemistry. Proc. Natl Acad. Sci. USA 104, 7764–7769 (2007).

    Article  Google Scholar 

  22. Gruhl, T. et al. Ultrafast structural changes direct the first molecular events of vision. Nature 615, 939–944 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jung, Y. O. et al. Volume-conserving transcis isomerization pathways in photoactive yellow protein visualized by picosecond X-ray crystallography. Nat. Chem. 5, 212–220 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fadini, A. et al. Serial femtosecond crystallography reveals that photoactivation in a fluorescent protein proceeds via the Hula Twist mechanism. J. Am. Chem. Soc. 145, 15796–15808 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saltiel, J. et al. Photoisomerization of all-cis-1,6-diphenyl-1,3,5-hexatriene in the solid state and in solution: a simultaneous three-bond twist process. Angew. Chem. Int. Ed. 48, 8082–8085 (2009).

    Article  CAS  Google Scholar 

  26. Gerwien, A., Mayer, P. & Dube, H. Photon-only molecular motor with reverse temperature-dependent efficiency. J. Am. Chem. Soc. 140, 16442–16445 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Gerwien, A., Schildhauer, M., Thumser, S., Mayer, P. & Dube, H. Direct evidence for Hula Twist and single-bond rotation photoproducts. Nat. Commun. 9, 2510 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Fischer, T. et al. Mechanistic elucidation of the Hula-Twist photoreaction in hemithioindigo. J. Am. Chem. Soc. 145, 14811–14822 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gerwien, A., Jehle, B., Irmler, M., Mayer, P. & Dube, H. An eight-state molecular sequential switch featuring a dual single-bond rotation photoreaction. J. Am. Chem. Soc. 144, 3029–3038 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bandara, H. M. D. & Burdette, S. C. Photoisomerization in different classes of azobenzene. Chem. Soc. Rev. 41, 1809–1825 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Den, A., Kar, R. K., Borin, V. A. & Schapiro, I. Insight into the isomerization mechanism of retinal proteins from hybrid quantum mechanics/molecular mechanics simulations. WIREs Comput. Mol. Sci. 12, e1562 (2022).

    Article  Google Scholar 

  32. Waldeck, D. H. Photoisomerization dynamics of stilbenes. Chem. Rev. 91, 415–436 (1991).

    Article  CAS  Google Scholar 

  33. Schultz, T. et al. Mechanism and dynamics of azobenzene photoisomerization. J. Am. Chem. Soc. 125, 8098–8099 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Nakatani, K., Sato, H. & Fukuda, R. A catalyzed E/Z isomerization mechanism of stilbene using para-benzoquinone as a triplet sensitizer. Phys. Chem. Chem. Phys. 24, 1712–1721 (2022).

    Article  CAS  PubMed  Google Scholar 

  35. Kochman, M. A., Palczewski, K. & Kubas, A. Theoretical study of the photoisomerization mechanism of all-trans-retinyl acetate. J. Phys. Chem. A 125, 8358–8372 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kemnitz, C. R. & Loewen, M. J. ‘Amide resonance’ correlates with a breadth of C–N rotation barriers. J. Am. Chem. Soc. 129, 2521–2528 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Ahmed, A. et al. Barriers to rotation about the chiral axis of tertiary aromatic amides. Tetrahedron 54, 13277–13294 (1998).

    Article  CAS  Google Scholar 

  38. Barrett, K. T., Metrano, A. J., Rablen, P. R. & Miller, S. J. Spontaneous transfer of chirality in an atropisomerically enriched two-axis system. Nature 509, 71–75 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bisz, E., Piontek, A., Dziuk, B., Szostak, R. & Szostak, M. Barriers to rotation in ortho-substituted tertiary aromatic amides: effect of chloro-substitution on resonance and distortion. J. Org. Chem. 83, 3159–3163 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Takahashi, H. et al. Atropisomerism observed in indometacin derivatives. Org. Lett. 13, 760–763 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Takahashi, Y. et al. Isolation of atropisomers of N-benzoylated pyrroles and imidazoles. Synthesis 47, 2125–2128 (2015).

    Article  CAS  Google Scholar 

  42. Palani, A. et al. Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonist. Bioorg. Med. Chem. Lett. 13, 705–708 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Kazmierski, W. M. et al. Biological and structural characterization of rotamers of C–C chemokine receptor type 5 (CCR5) inhibitor GSK214096. ACS Med. Chem. Lett. 5, 1296–1299 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lorentzen, M. et al. Atropisomerism in tertiary biaryl 2-amides: a study of Ar–CO and Ar–Ar′ rotational barriers. J. Org. Chem. 82, 7300–7308 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Choudhary, A. & Raines, R. T. An evaluation of peptide-bond isosteres. ChemBioChem 12, 1801–1807 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Radael, G. N. & Pontes, R. M. An energy decomposition analysis approach to the rotational barriers of amides and thioamides. Comput. Theor. Chem. 1187, 112938 (2020).

    Article  CAS  Google Scholar 

  47. Kaur, D., Sharma, P., Bharatam, P. V. & Dogra, N. Substituent and solvent effects on the rotational barriers in selenoamides: a theoretical study. J. Mol. Struct. THEOCHEM 759, 41–49 (2006).

    Article  CAS  Google Scholar 

  48. Helbing, J. et al. A fast photoswitch for minimally perturbed peptides: investigation of the transcis photoisomerization of N-methylthioacetamide. J. Am. Chem. Soc. 126, 8823–8834 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Huang, Y., Cong, Z., Yang, L. & Dong, S. A photoswitchable thioxopeptide bond facilitates the conformation-activity correlation study of insect kinin. J. Pept. Sci. 14, 1062–1068 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Shim, S. C. & Lee, S. J. Rotational photoisomerization of a thioamide, N-5-trifluoromethyl-6-methoxy-1-thionaphtoyl-N-methylglycine. Bull. Korean Chem. Soc. 9, 236–240 (1988).

    CAS  Google Scholar 

  51. Prasad, B. V., Uppal, P. & Bassi, P. S. Barrier to C–N rotation in selenoformamide: an ab initio study. Chem. Phys. Lett. 276, 31–38 (1997).

    CAS  Google Scholar 

  52. Nieuwland, C. & Guerra, C. F. How the chalcogen atom size dictates the hydrogen-bond donor capability of carboxamides, thioamides, and selenoamides. Chem. Eur. J. 28, e202200755 (2022).

    Article  CAS  PubMed  Google Scholar 

  53. Meca, L., Řeha, D. & Havlas, Z. Racemization barriers of 1,1′-binaphthyl and 1,1′-binaphthalene-2,2′-diol: a DFT study. J. Org. Chem. 68, 5677–5680 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Zhang, T. et al. Pyrene-based metal–organic framework NU-1000 photocatalysed atom-transfer radical addition for iodoperfluoroalkylation and (Z)-selective perfluoroalkylation of olefins by visible-light irradiation. RSC Adv. 8, 32610–32620 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Merten, C., Golub, T. P. & Kreienborg, N. M. Absolute configurations of synthetic molecular scaffolds from vibrational CD spectroscopy. J. Org. Chem. 84, 8797–8814 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Batista, J. M. Jr, Blanch, E. W. & da Silva Bolzani, V. Recent advances in the use of vibrational chiroptical spectroscopic methods for stereochemical characterization of natural products. Nat. Prod. Rep. 32, 1280–1302 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Scholten, K., Engelage, E. & Merten, C. Basis set dependence of S=O stretching frequencies and its consequences for IR and VCD spectra predictions. Phys. Chem. Chem. Phys. 22, 27979–27986 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Maeda, S., Taketsugu, T. & Morokuma, K. Exploring transition state structures for intramolecular pathways by the artificial force induced reaction method. J. Comput. Chem. 35, 166–173 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Harabuchi, Y., Hatanaka, M. & Maeda, S. Exploring approximate geometries of minimum energy conical intersections by TDDFT calculations. Chem. Phys. Lett. 737, 100007 (2019).

    Article  Google Scholar 

  60. Liang, R. & Bakhtiiari, A. Effects of enzyme–ligand interactions on the photoisomerization of a light-regulated chemotherapeutic drug. J. Phys. Chem. B 126, 2382–2393 (2022).

    Article  CAS  PubMed  Google Scholar 

  61. Schrödinger release 2020-3: MacroModel. Schrödinger https://www.schrodinger.com/releases/release-2020-3 (2020).

  62. Polak, E. & Ribiere, G. Revenue francaise informatique. Recherche Opérationnelle 16, 35–43 (1969).

  63. Roos, K. et al. OPLS3e: extending force field coverage for drug-like small molecules. J. Chem. Theory Comput. 15, 1863–1874 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. Frisch, M. J. et al. Gaussian 16, Revision C.01 (Gaussian, 2016).

  65. Dennington, R., Keith, T. A. & Millam, J. M. GaussView, Version 6 (Semichem, 2016).

  66. Werner, H.-J. et al. A Package of Ab Initio Programs (MOLPRO, 2019).

  67. GRRM20. HPC Systems https://www.hpc.co.jp/chem/software/grrm20_e (2020).

  68. Maeda, S. & Harabuchi, Y. Exploring paths of chemical transformations in molecular and periodic systems: an approach utilizing force. WIREs Comput. Mol. Sci. 11, e1538 (2021).

    Article  CAS  Google Scholar 

  69. Maeda, S. et al. Implementation and performance of the artificial force induced reaction method in the GRRM17 program. J. Comput. Chem. 39, 233–251 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. ; Legault, C. Y. CYLview20. Université de Sherbrooke http://www.cylview.org (2020).

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Acknowledgements

This research was supported in part by JSPS KAKENHI Grant-in-Aid for Challenging Research (Exploratory) (S.I., grant number JP18K19384), Grant-in-Aid for Scientific Research (B) (T.T., grant number JP18K19384), Grant Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (S.I., grant number JP22ama121039) a Grant-in-Aid for Challenging Research (Exploratory) (Y.H., 22K19002), JST-FOREST (Y.H.), JST-ERATO (S.M. and Y.H., JPMJER1903), and JSPS-WPI and The Akiyama Life Science Foundation (A.K.), and was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under ‘Support Program for Implementation of New Equipment Sharing System’. Part of the results was computed at the supercomputer system at the information initiative centre in Hokkaido University. We thank T. Mita (Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Japan) and Y. Inokuma (Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Japan) for helpful discussion on the photochemistry. We thank M. Jin (Institute for Chemical Reaction Design and Discovery (WPI-ICReDD)) for helpful discussion and providing instrument for quantum yield determination.

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Contributions

A.K. and. S.I. designed the research and A.K., R.K and S.I designed the experiments. A.K., Y.H. and S.M. performed calculation. S.N., R.K. and T.A. prepared compounds, acquired experimental data for the isomerization and measured the UV spectra. S.N., T.A. and A.K. analysed experimental data for the isomerization. T.T. and K.M. measured the VCD spectra. S.N., A.K., R.K., T.A., Y.H., T.T., K.M., S.M. and S.I. wrote the paper. All authors discussed the results and commented on the paper and have given approval to the final version of the manuscript.

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Correspondence to Satoshi Ichikawa or Akira Katsuyama.

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Extended data

Extended Data Fig. 1 Photo-induced isomerization of the chalcogen amides.

a, Kinetic parameters of the Z to E isomerization. Means and standard deviations are shown for three independent experiments. The variations from the standard condition were also shown. b, Kinetics of the racemization under the photochemical conditions. Means and standard deviations are shown for three independent experiments.

Extended Data Fig. 2 Thermal or photoinduced isomerization of two isomers of 1-S.

a, The time courses of the isomerization of the Z-(R)-1-S under a thermal condition. The circles indicate experimental ratio of each isomer at each time, and the dotted lines connect adjacent points. b, The time courses of the photo-induced isomerization of the Z-(S)-1-S. Three individual experiments were performed, and the representative data are presented. The circles indicate experimental ratio of each isomer at each time, and the dotted lines connect adjacent points.

Source data

Extended Data Fig. 3 Photoinduced isomerization of E-(R)-1-S.

Comparison of chiral HPLC chromatograms of isomerization after 2 minutes and 24 hours, and under oxygen atmosphere.

Source data

Extended Data Fig. 4 Quantum yields for the isomerization of E-(R)-7-S and Z-(S)-7-S.

a, Chiral HPLC chromatograms of isolated Z-(S)-7-S, Z-(R)-7-S, E-(S)-7-S and E-(R)-7-S. b, VCD spectra of each stereoisomer of 7-S. Absolute stereochemistry was determined by comparing theoretical and experimental spectra. c, Quantum yields were determined at 365 nm. Representative data are presented from the three individual experiments. Linear behavior was observed in the initial stage of the isomerization, and quantum yields were determined from the kinetics parameter. Means are shown for the three independent experiments.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–507, Tables 1–23, methods and discussion.

Supplementary Data 1

Cartesian coordinates for the calculated structures.

Source data

Source data for all figures and Extended Data figures

Raw data for Figs. 2–5 and Extended Data Figs 2–4.

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Nagami, S., Kaguchi, R., Akahane, T. et al. Photoinduced dual bond rotation of a nitrogen-containing system realized by chalcogen substitution. Nat. Chem. 16, 959–969 (2024). https://doi.org/10.1038/s41557-024-01461-9

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