Synthesis of Chlorophyll–Thiophene Conjugates through Friedel–Crafts Reaction

Abstract

Friedel–Crafts reactions of a chlorophyll-a derivative possessing a hydroxymethyl group at the 3-position with (benzo)thiophenes in the presence of p-toluenesulfonic acid gave 3-(benzo)thienylmethyl-chlorins regioselectively. The α-position of unsubstituted thiophene was more reactive toward the acid-assisted dehydration reaction than the β-position. Electron-donating substituents at the β-position in thiophene were acceptable for the production of the α-adducts, but electron-withdrawing substitution on the thiophene core proved ineffective. The electron-rich α,α′-dimethylthiophene could not be substituted at the β-position with the (chlorin-3-yl)methyl group. The reaction with benzothiophene exclusively afforded the β-substituted adduct. The reverse regioselectivity was consistent with the conventional electrophilic substitutions of (benzo)thiophenes. Under the aforementioned Friedel–Crafts reaction conditions, the α-methylation of benzothiophene led to the β-adduct as expected, whereas its β-methylation resulted in the successful preparation of the α-adduct. The fusion of a benzo moiety on thiophene largely affected the reactivity and regioselectivity toward the production of the chlorophyll–thiophene conjugates.

Key words

chlorin π-system - dehydration adduct - electrophilic substitution - heteroaromatic - methyl pyropheophorbide-a - regioselectivity

Publikationsverlauf

Eingereicht: 26. Dezember 2024

Angenommen nach Revision: 27. Januar 2025

Accepted Manuscript online:
27. Januar 2025

Artikel online veröffentlicht:
10. März 2025

• References

• 1a Thiophene and Its Derivatives, Part One. Gronowitz S. Wiley; New York: 1985
• 1b Thiophene and Its Derivatives, Part Two. Gronowitz S. Wiley; New York: 1986
• 1c Fukushima K, Yasukawa M, Muto N, Uemura H, Ishiwatari R. Org. Geochem. 1992; 18: 83
• 1d Thiophenes . Joule JA. Springer; Heidelberg: 2015
• 1e Barbarella G, Zangoli M, Di Maria F. Adv. Heterocycl. Chem. 2017; 123: 105
• 1f Nowicki J, Wójcik J, Muszyński M, Woszczyński P. Catal. Commun. 2019; 132: 105811
• 1g da Cruz RM. D, Mendonça-Junior FJ. B, de Mélo NB, Scotti L, de Araújo RS. A, de Almeida RN, de Moura RO. Pharmaceuticals 2021; 14: 692
• 1h Wu H, Lu X, Xu J, Zhang X, Li Z, Yang X, Ling Y. Molecules 2022; 27: 8700
• 1i Idrissi A, Fakir ZE, Atir R, Habsaoui A, Touhami ME, Bouzakraoui S. Mater. Chem. Phys. 2023; 293: 126851
• 1j Gorbunova IA, Timofeeva M, Gunina E, Sharavyeva YO, Parkhoma KY, Shipilovskikh DA, Shipilovskikh SA. Photonics Nanostructures: Fundam. Appl. 2024; 58: 101220
• 2a Björn LO, Papageorgiou GC, Blankenship RE. Govindjee, Photosynth. Res. 2009; 99: 85
• 2b Ryan AA, Senge MO. Photochem. Photobiol. Sci. 2015; 14: 638
• 2c Duan S, Zhou Q, Li A, Wang X.-F, Sasaki S, Tamiaki H. Solar RRL 2020; 4: 2000162
• 2d Bryant DA, Hunter CN, Warren MJ. J. Biol. Chem. 2020; 295: 6888
• 2e Govindjee, Stirbet A, Lindsey JS, Scheer H. Photosynth. Res. 2024; 160: 55
• 2f Tamiaki H, Kichishima S. Plant Cell Physiol. 2025; 66: 153
• 3a Gunderson VL, Wasielewski MR. Handbook Porphyr. Sci. 2012; 20: 45
• 3b Otsuki J. J. Mater. Chem. A 2018; 6: 6710
• 3c Kichishima S, Maeda H, Tamiaki H. J. Phys. Org. Chem. 2023; 36: e4546
• 4 Osuka A, Wada Y, Shinoda S. Tetrahedron 1996; 52: 4311
• 5a Kinoshita Y, Kitagawa Y, Tamiaki H. Chem. Eur. J. 2016; 22: 9996
• 5b Ishii T, Matsubara S, Tamiaki H. Chem. Commun. 2023; 59: 1967
• 6 Ohashi K, Kinoshita Y, Tamiaki H. Tetrahedron 2018; 74: 2703
• 7 Kim N.-R, Kim S, Kim JD, Huh DS, Shim YK, Choe SJ. Bull. Korean Chem. Soc. 2009; 30: 205
• 8a Helaja J, Tauber AY, Abel Y, Tkachenko NV, Lemmetyinen H, Kilpeläinen I, Hynninen PH. J. Chem. Soc., Perkin Trans. 1 1999; 2403
• 8b Holzwarth AR, Katterle M, Müller MG, Ma Y.-Z, Prokhorenko V. Pure Appl. Chem. 2001; 73: 469
• 8c Lee J.-C, Kim T.-Y, Kang SH, Shim YK. Bull. Korean Chem. Soc. 2001; 22: 257
• 8d Shinozaki Y, Uragami C, Hashimoto H, Tamiaki H. Chem. Eur. J. 2020; 26: 8897
• 9 Johnson DG, Niemczyk MP, Minsek DW, Wiederrecht GP, Svec WA, Gaines GL. III, Wasielewski MR. J. Am. Chem. Soc. 1993; 115: 5692
• 10a Tkachenko NV, Tauber AY, Hynninen PH, Sharonov AY, Lemmetyinen H. J. Phys. Chem. A. 1999; 103: 3657
• 10b Kichishima S, Funayama N, Tamiaki H. Dyes Pigm. 2024; 227: 112193
• 11a Numata M, Kinoshita D, Taniguchi N, Tamiaki H, Ohta A. Angew. Chem. Int. Ed. 2012; 51: 1844
• 11b Shinozaki Y, Richards G, Ogawa K, Yamano A, Ohara K, Yamaguchi K, Kawano S, Tanaka K, Araki Y, Wada T, Otsuki J. J. Am. Chem. Soc. 2013; 135: 5262
• 11c Liang B, Liu Y, Xu X, Jin Y, Qi C, Wang J. Chin. J. Org. Chem. 2013; 33: 2357
• 11d Yamamoto Y, Tamiaki H. Dyes Pigm. 2015; 118: 159
• 11e Shinozaki Y, Ohkubo K, Fukuzumi S, Sugawa K, Otsuki J. Chem. Eur. J. 2016; 22: 1165
• 11f Takarada Y, Hara N, Ogasawara S, Tamiaki H. J. Porphyr. Phthalocyanines 2023; 27: 1189
• 12 Wang J.-J, Wu X.-R, Wang L.-M, Han G.-F, Shim YK. Chin. J. Org. Chem. 2004; 24: 906
• 13 Kudo R, Hanayama H, Vedhanarayanan B, Tamiaki H, Hara N, Rogers SE, Hollamby MJ, Biplab M, Harano K, Yagai S. Org. Chem. Front. 2024; 11: 6304
• 14a Galindev O, Badraa N, Dalantai M, Sengee G.-I, Dorjnamjin D, Shim YK. Photochem. Photobiol. Sci. 2008; 7: 1273
• 14b Wang J.-J, Liu C, Wu J, Liu R.-R, Zhang P. J. Heterocycl. Chem. 2014; 51: 392
• 14c Kinoshita Y, Tamiaki H. J. Photochem. Photobiol. A: Chem. 2015; 313: 27
• 15 Wang J.-J, Wu X.-R, Han G.-F, Shim YK. Chin. J. Org. Chem. 2005; 25: 313
• 16a Wasielewski MR, Svec WA, Cope BT. J. Am. Chem. Soc. 1978; 100: 1961
• 16b Johnson DG, Svec WA, Wasielewski MR. Isr. J. Chem. 1988; 28: 193
• 16c Wasielewski MR, Johnson DG, Niemczyk MP, Gaines GL. III, O’Neil MP, Svec WA. J. Am. Chem. Soc. 1990; 112: 6482
• 16d Wiederrecht GP, Watanabe S, Wasielewski MR. Chem. Phys. 1993; 176: 601
• 16e Kosaka N, Tamiaki H. Eur. J. Org. Chem. 2004; 2325
• 16f Sasaki S, Tamiaki H. Tetrahedron Lett. 2006; 47: 4965
• 16g Kataoka Y, Shibata Y, Tamiaki H. Chem. Lett. 2010; 39: 953
• 16h Sasaki S, Mizutani K, Kunieda M, Tamiaki H. Tetrahedron 2011; 67: 6065
• 16i Belyaev ES, Kozhemyakin GL, Tyurin VS, Frolova VV, Lonin IS, Ponomarev GV, Buryak AK, Zamilatskov IA. Org. Biomol. Chem. 2022; 20: 1926
• 17a Wang J.-J, Shim YK, Jiang G.-J, Imafuku K. J. Heterocycl. Chem. 2003; 40: 1075
• 17b Wang J.-J, Lee K.-I, Kim M.-H, Shim YK. Bull. Korean Chem. Soc. 2004; 25: 1449
• 18 Tamiaki H, Amakawa M, Shimono Y, Tanikaga R, Holzwarth AR, Schaffner K. Photochem. Photobiol. 1996; 63: 92
• 19 Sakaguchi K, Tamiaki H. Tetrahedron 2022; 123: 132981
• 20 Limberakis C. Tetrahedron Org. Chem. Ser. 2007; 26: 251