Flavins have been established as effective catalysts in oxidative photoredox catalysis. Conversely, their use in reductive photocatalysis remains limited, mainly due to the relatively low stability of the transient flavin radicals (semiquinones), which are used in photoreductions. The fully reduced forms of flavins are also disadvantaged in photocatalysis because they absorb light in the UV rather than in the visible region. In this work, we present a new approach for reductive flavin photocatalysis that utilises a flavin (isoalloxazine) anion derived from the elusive 10-unsubstituted 3,7,8-trimethylisoalloxazine, an unstable tautomer of 3-methyllumichrome. We found the conditions under which this isoalloxazine anion is formed by in situ deprotonation/isomerisation from the readily available 3-methyllumichrome and we subsequently used it as a photoredox catalyst in the reductive dehalogenation of activated bromoarenes and their C-P coupling reaction with trimethyl phosphite to form an arylphosphonate. Steady-state and transient absorption spectroscopy, NMR and cyclic voltammetry investigations, together with quantum chemical calculations, showed that the anion of oxidised isoalloxazine has several advantages, compared to other forms of flavins used in photoreductions, such as high stability, even in the presence of oxygen, an absorption maximum in the visible region, thereby allowing the use of excitation light between 470 and 505 nm, and a relatively long-lived singlet excited-state.

Central Laboratories University of Chemistry and Technology Prague 16628 Prague Czech Republic

Department of Molecular Electrochemistry and Catalysis J Heyrovský Institute of Physical Chemistry Czech Academy of Sciences 18223 Prague Czech Republic

Department of Organic Chemistry University of Chemistry and Technology Prague 16628 Prague Czech Republic

Faculty of Chemistry Adam Mickiewicz University 61 614 Poznań Poland

Faculty of Physics and Astronomy Adam Mickiewicz University 61 614 Poznań Poland

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Pimviriyakul P. and Chaiyen P., in The Enzymes, ed. P. Chaiyen and F. Tamanoi, Academic Press, 2020, pp. 1–36

Drenth J. and Fraaije M. W., in Flavin-Based Catalysis, ed. R. Cibulka and M. Fraaije, Wiley, 2021, pp. 29–65

Walsh C. T. Wencewicz T. A. Nat. Prod. Rep. 2013;30:175–200. doi: 10.1039/C2NP20069D. PubMed DOI PMC

Ahmad I. and Vaid F. H. M., in Flavins, ed. E. Silva and A. M. Edwards, Royal Society of Chemistry, 2006, pp. 13–40

Lopez L. Fasano C. Perrella G. Facella P. Genes. 2021;12:672. doi: 10.3390/genes12050672. PubMed DOI PMC

Brodl E. Winkler A. Macheroux P. Comput. Struct. Biotechnol. J. 2018;16:551–564. doi: 10.1016/j.csbj.2018.11.003. PubMed DOI PMC

Christie J. M. Murphy A. S. Am. J. Bot. 2013;100:35–46. doi: 10.3732/ajb.1200340. PubMed DOI

Sancar A. Angew. Chem., Int. Ed. 2016;55:8502–8527. doi: 10.1002/anie.201601524. PubMed DOI

Sorigué D. Légeret B. Cuiné S. Blangy S. Moulin S. Billon E. Richaud P. Brugière S. Couté Y. Nurizzo D. Müller P. Brettel K. Pignol D. Arnoux P. Li-Beisson Y. Peltier G. Beisson F. Science. 2017;357:903–907. doi: 10.1126/science.aan6349. PubMed DOI

Grosheva D. and Hyster T. K., in Flavin-Based Catalysis, ed. R. Cibulka and M. Fraaije, Wiley, 2021, pp. 291–313

Fu H. Hyster T. K. Acc. Chem. Res. 2024;57:1446–1457. doi: 10.1021/acs.accounts.4c00129. PubMed DOI PMC

Simić S. Jakštaitė M. Huck W. T. S. Winkler C. K. Kroutil W. ACS Catal. 2022;12:14040–14049. doi: 10.1021/acscatal.2c04444. PubMed DOI PMC

Emmanuel M. A. Bender S. G. Bilodeau C. Carceller J. M. DeHovitz J. S. Fu H. Liu Y. Nicholls B. T. Ouyang Y. Page C. G. Qiao T. Raps F. C. Sorigué D. R. Sun S.-Z. Turek-Herman J. Ye Y. Rivas-Souchet A. Cao J. Hyster T. K. Chem. Rev. 2023;123:5459–5520. doi: 10.1021/acs.chemrev.2c00767. PubMed DOI PMC

Harrison W. Huang X. Zhao H. Acc. Chem. Res. 2022;55:1087–1096. doi: 10.1021/acs.accounts.1c00719. PubMed DOI

Alphand V. van Berkel W. J. H. Jurkaš V. Kara S. Kourist R. Kroutil W. Mascia F. Nowaczyk M. M. Paul C. E. Schmidt S. Spasic J. Tamagnini P. Winkler C. K. ChemPhotoChem. 2023;7:e202200325. doi: 10.1002/cptc.202200325. DOI

Dong J. Fernández-Fueyo E. Hollmann F. Paul C. E. Pesic M. Schmidt S. Wang Y. Younes S. Zhang W. Angew. Chem., Int. Ed. 2018;57:9238–9261. doi: 10.1002/anie.201800343. PubMed DOI PMC

Srinivasan S. J. Cleary S. E. Ramirez M. Reeve H. Paul C. Vincent K. A. Angew. Chem., Int. Ed. 2021;60:13824–13828. doi: 10.1002/anie.202101186. PubMed DOI PMC

Svobodová E. and Cibulka R., in Flavin-Based Catalysis, ed. R. Cibulka and M. Fraaije, Wiley, 2021, pp. 265–291

König B. Kümmel S. Svobodová E. Cibulka R. Phys. Sci. Rev. 2018;3:20170168. doi: 10.1515/psr-2017-0168. DOI

Sideri I. K. Voutyritsa E. Kokotos C. G. Org. Biomol. Chem. 2018;16:4596–4614. doi: 10.1039/C8OB00725J. PubMed DOI

Rehpenn A. Walter A. Storch G. Synthesis. 2021;53:2583–2593. doi: 10.1055/a-1458-2419. DOI

Cheng B. and König B., in Flavin-Based Catalysis, ed. R. Cibulka and M. Fraaije, Wiley, 2021, pp. 245–264

Langschwager T. Storch G. Angew. Chem., Int. Ed. 2024;64:e202414679. doi: 10.1002/anie.202414679. PubMed DOI

Walter A. Eisenreich W. Storch G. Angew. Chem., Int. Ed. 2023;62:e202310634. doi: 10.1002/anie.202310634. PubMed DOI

Shiogai Y. Oka M. Miyake H. Iida H. Org. Biomol. Chem. 2024;22:4450–4454. doi: 10.1039/D4OB00360H. PubMed DOI

Shen D. Zhong F. Li L. Zhang H. Ren T. Sun C. Wang B. Guo M. Chao M. Fukuzumi S. Org. Chem. Front. 2023;10:2653–2662. doi: 10.1039/D3QO00375B. DOI

Immel J. R. Alghafli B. M. Rodríguez Ugalde A. A. Bloom S. Org. Lett. 2023;25:3818–3822. doi: 10.1021/acs.orglett.3c01398. PubMed DOI PMC

Bera N. Lenka B. S. König B. Sarkar D. J. Org. Chem. 2023;88:7977–7987. doi: 10.1021/acs.joc.2c03037. PubMed DOI

Trenker S. Grunenberg L. Banerjee T. Savasci G. Poller L. M. Muggli K. I. M. Haase F. Ochsenfeld C. Lotsch B. V. Chem. Sci. 2021;12:15143–15150. doi: 10.1039/D1SC04143F. PubMed DOI PMC

Pokluda A. Anwar Z. Boguschová V. Anusiewicz I. Skurski P. Sikorski M. Cibulka R. Adv. Synth. Catal. 2021;363:4371–4379. doi: 10.1002/adsc.202100024. DOI

Obertík R. Ludvíková L. Chudoba J. Cibulka R. ChemCatChem. 2025;17:e202401795. doi: 10.1002/cctc.202401795. DOI

Foja R. Walter A. Jandl C. Thyrhaug E. Hauer J. Storch G. J. Am. Chem. Soc. 2022;144:4721–4726. doi: 10.1021/jacs.1c13285. PubMed DOI

Pavlovska T. Weisheitelová I. Pramthaisong C. Sikorski M. Jahn U. Cibulka R. Adv. Synth. Catal. 2023;365:4662–4671. doi: 10.1002/adsc.202300843. DOI

Pavlovska T. Král Lesný D. Svobodová E. Hoskovcová I. Archipowa N. Kutta R. J. Cibulka R. Chem.–Eur. J. 2022;28:e202200768. doi: 10.1002/chem.202200768. PubMed DOI PMC

Obertík R. Chudoba J. Šturala J. Tarábek J. Ludvíková L. Slanina T. König B. Cibulka R. Chem.–Eur. J. 2022;28:e202202487. doi: 10.1002/chem.202202487. PubMed DOI

Graml A. Neveselý T. Kutta R. J. Cibulka R. König B. Nat. Commun. 2020;11:3174. doi: 10.1038/s41467-020-16909-y. PubMed DOI PMC

Kao Y.-T. Saxena C. He T.-F. Guo L. Wang L. Sancar A. Zhong D. J. Am. Chem. Soc. 2008:13132–13139. doi: 10.1021/ja8045469. PubMed DOI PMC

Su D. Kabir M. P. Orozco-Gonzalez Y. Gozem S. Gadda G. ChemBioChem. 2019;20:1614. doi: 10.1002/cbic.201900373. PubMed DOI

Kabir M. P. Orozco-Gonzalez Y. Gozem S. Phys. Chem. Chem. Phys. 2019;21:16526–16537. doi: 10.1039/C9CP02230A. PubMed DOI

Huang X. Wang B. Wang Y. Jiang G. Feng J. Zhao H. Nature. 2020;584:69–74. doi: 10.1038/s41586-020-2406-6. PubMed DOI

Page C. G. Cao J. Oblinsky D. G. MacMillan S. N. Dahagam S. Lloyd R. M. Charnock S. J. Scholes G. D. Hyster T. K. J. Am. Chem. Soc. 2023;147:11866–11874. doi: 10.1021/jacs.3c03607. PubMed DOI PMC

Sandoval B. A. Clayman P. D. Oblinsky D. G. Oh S. Nakano Y. Bird M. Scholes G. D. Hyster T. K. J. Am. Chem. Soc. 2021;143:1735–1739. doi: 10.1021/jacs.0c11494. PubMed DOI

Biegasiewicz K. F. Cooper S. J. Gao X. Oblinsky D. G. Kim J. H. Garfinkle S. E. Joyce L. A. Sandoval B. A. Scholes G. D. Hyster T. K. Science. 2019;364:1166–1169. doi: 10.1126/science.aaw1143. PubMed DOI PMC

Bartolomei B. Gentile G. Rosso C. Filippini G. Prato M. Chem.–Eur. J. 2021;27:16062–16070. doi: 10.1002/chem.202102276. PubMed DOI

Wu S. Schiel F. Melchiorre P. Angew. Chem., Int. Ed. 2023;62:e202306364. doi: 10.1002/anie.202306364. PubMed DOI

Schmalzbauer M. Marcon M. König B. Angew. Chem., Int. Ed. 2021;60:6270–6292. doi: 10.1002/anie.202009288. PubMed DOI PMC

Sheldrick A. Müller D. Günther A. Nieto P. Dopfer O. Phys. Chem. Chem. Phys. 2018;20:7407–7414. doi: 10.1039/C8CP00590G. PubMed DOI

Song P.-S. Sun M. Koziolowa A. Koziol J. J. Am. Chem. Soc. 1974;96:4319–4323. doi: 10.1021/ja00820a045. DOI

Koziołowa A. Photochem. Photobiol. 1979;29:459–471. doi: 10.1111/j.1751-1097.1979.tb07076.x. DOI

Mal M. Mandal D. J. Photochem. Photobiol., A. 2021;404:112888. doi: 10.1016/j.jphotochem.2020.112888. DOI

Prukała D. Khmelinskii I. Koput J. Gierszewski M. Pędziński T. Sikorski M. Photochem. Photobiol. 2014;90:972–988. doi: 10.1111/php.12289. PubMed DOI

Sikorska E. Khmelinskii I. Hoffmann M. Machado I. F. Ferreira L. F. V. Dobek K. Karolczak J. Krawczyk A. Insińska-Rak M. Sikorski M. J. Phys. Chem. A. 2005;109:11707–11714. doi: 10.1021/jp053951d. PubMed DOI

Miskolczy Z. Biczók L. Görner H. J. Photochem. Photobiol., A. 2009;207:47–51. doi: 10.1016/j.jphotochem.2008.12.012. DOI

Prukała D. Sikorska E. Koput J. Khmelinskii I. Karolczak J. Gierszewski M. Sikorski M. J. Phys. Chem. A. 2012;116:7474–7490. doi: 10.1021/jp300522h. PubMed DOI

Tyagi A. Penzkofer A. Photochem. Photobiol. 2011;87:524–533. doi: 10.1111/j.1751-1097.2010.00836.x. PubMed DOI

Penzkofer A. J. Photochem. Photobiol., A. 2016;314:114–124. doi: 10.1016/j.jphotochem.2015.08.011. DOI

Barišić D. Tomišić V. Bregović N. Anal. Chim. Acta. 2019;1046:77–92. doi: 10.1016/j.aca.2018.09.026. PubMed DOI

Müller F. Dudley K. H. Helv. Chim. Acta. 1971;54:1487–1497. doi: 10.1002/hlca.19710540534. PubMed DOI

Kuhn R. Moruzzi G. Ber. Dtsch. Chem. Ges. 1934;67:888–891. doi: 10.1002/cber.19340670539. DOI

Sikorska E. Khmelinskii I. V. Prukała W. Williams S. L. Patel M. Worrall D. R. Bourdelande J. L. Koput J. Sikorski M. J. Phys. Chem. A. 2004;108:1501–1508. doi: 10.1021/jp037048u. DOI

Magdesieva T. V. Kukhareva I. I. Artamkina G. A. Butin K. P. Beletskaya I. P. J. Organomet. Chem. 1994;468:213–221. doi: 10.1016/0022-328X(94)80052-9. DOI

Májek M. Filace F. Jacobi von Wangelin A. Chem.–Eur. J. 2015;21:4518–4522. doi: 10.1002/chem.201406461. PubMed DOI

Till N. A. Tian L. Dong Z. Scholes G. D. MacMillan D. W. C. J. Am. Chem. Soc. 2020;142:15830–15841. doi: 10.1021/jacs.0c05901. PubMed DOI

Neumeier M. Sampedro D. Májek M. de la Peña O’Shea V. A. Wangelin A. J. v. Pérez-Ruiz R. Chem.–Eur. J. 2018;24:105–108. doi: 10.1002/chem.201705326. PubMed DOI

Enemærke R. J. Christensen T. B. Jensen H. Daasbjerg K. J. Chem. Soc., Perkin Trans. 2. 2001:1620–1630. doi: 10.1039/B102835A. DOI

Wang C. Li H. Bürgin T. H. Wenger O. S. Nat. Chem. 2024;16:1151–1159. doi: 10.1038/s41557-024-01482-4. PubMed DOI PMC

Rehpenn A. Hindelang S. Truong K.-N. Pöthig A. Storch G. Angew. Chem., Int. Ed. 2024;63:e202318590. doi: 10.1002/anie.202318590. PubMed DOI

Gary S. Woolley J. Goia S. Bloom S. Chem. Sci. 2024;15:11444–11454. doi: 10.1039/D4SC03054K. PubMed DOI PMC

Das D. Miller A.-F. Chem. Sci. 2024;15:7610–7622. doi: 10.1039/D4SC01642D. PubMed DOI PMC

Worner J. Panter S. Illarionov B. Bacher A. Fischer M. Weber S. Angew. Chem., Int. Ed. 2023;62:e202309334. doi: 10.1002/anie.202309334. PubMed DOI

Romero N. A. Nicewicz D. A. Chem. Rev. 2016;116:10075–10166. doi: 10.1021/acs.chemrev.6b00057. PubMed DOI