# Fileset [HILL_Ms_jpp220284_R1.pdf](https://mdr.nims.go.jp/filesets/d87bdce7-c055-45bd-98f5-a33a81e994e1/download) ## Creator Jan Hynek, Mandeep K. Chahal, [Daniel T. Payne](https://orcid.org/0000-0001-7707-8381), Anuradha Liyanage, Francis D’Souza, [Jonathan P. Hill](https://orcid.org/0000-0002-4229-5842) ## Rights Electronic version of an article published as Journal of Porphyrins and Phthalocyanines,27,07n10,2023,1108-1118,10.1142/S1088424623500359, © World Scientific Publishing Company, https://doi.org/10.1142/S1088424623500359.[In Copyright](http://rightsstatements.org/vocab/InC/1.0/) ## Other metadata [Design rules for oxoporphyrinogen (‘OxP’) as a versatile chromophore for efficient singlet oxygen generation](https://mdr.nims.go.jp/datasets/839522e6-8cfc-41e2-8f9c-6f380ec6a426) ## Fulltext Template for Electronic Submission to JPP JournalsDesign rules for oxoporphyrinogen (‘OxP’) as a versatile chromophore for efficient singlet oxygen generation Jan Hyneka†, Mandeep K. Chahala†, Daniel T. Payne*a,b†, Anuradha Liyanagec, Francis D’Souzac and Jonathan P. Hill*a aInternational Center for Materials Nanoarchitectonics, National Institute for Materials Science, Namiki 1-1, Tsukuba., Ibaraki 305-0044, Japan bInternational Center for Young Scientists, National Institute for Materials Science, Sengen 1-2-1, Tsukuba., Ibaraki 305-0047, Japan cDepartment of Chemistry, University of North Texas, 1155 Union Circle, 305070 Denton, Texas 76203, USA. Received date (to be automatically inserted after your manuscript is submitted) Accepted date (to be automatically inserted after your manuscript is accepted) ABSTRACT: Meso-5,10,15,20-tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylideneporphyrinogen, OxP, is a versatile, highly colored chromophore with strong broad absorption in the visible range. It is derived from meso-5,10,15,20-tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin by two-electron oxidation, and the OxP tetrapyrrole moiety exists in a saddle conformation. N-Alkylation of the OxP core nitrogen atoms can be used to functionalize the chromophore leading to a class of stable molecules with highly substituted peripheries. Substituted OxPs can act as singlet oxygen generators under light irradiation and the efficacy of this process is influenced by the multiplicity of N-substitution, and by the chemical identity of those substituents. Bromination of the macrocyclic β-positions can also be used to control singlet oxygen generation by the relevant derivatives. We report the quantum yields of singlet oxygen generation for a series of differently substituted OxP derivatives whose metrics indicate that these compounds possess significant potential in the corresponding applications including photodynamic therapy, bacterial inactivation therapy, and organic transformations. KEYWORDS: Oxoporphyrinogen, porphyrinoid, singlet oxygen generator. *Correspondence to: Daniel T. Payne, e–mail: Daniel.Payne@open.ac.uk; Jonathan P. Hill, e–mail: Jonathan.Hill@nims.go.jp, tel.: +81–29–860–4399. †Current address: (J. H.): Institute of Inorganic Chemistry, Czech Academy of Sciences, 250 68 Husinec-Řež, Czech Republic; (M. K. C.): Department of Chemistry, University of Southampton, University Road, Southampton, SO17 1BJ, United Kingdom; (D. T. P.) School of Life, Health and Chemical Science, Open University, Walton Hall, Milton Keynes, MK7 6AA, United Kingdom INTRODUCTION Oxoporphyrinogen, OxP, is a highly colored tetrapyrrole chromophore obtained by the aerial oxidation of the porphyrin (TDtBHPP)1 under acidic2 or, more usually, basic conditions.3 Redox transformations involving OxP/TDtBHPP have been studied revealing potential catalytic properties.4,5 OxP and its N-alkylated derivatives exhibit broad electronic absorption across most of the visible range, undergo reversible redox processes,6,7 and have a saddle-shaped macrocycle (similar but not identical to calix[4]pyrrole8), which facilitates electronic conjugation between its different component groups. The OxP chromophore is synthetically flexible with augmentation possible by simple N-alkylation,6,7 variation of meso-substituents,9,10, and substitution at macrocyclic β-positions.11,12 Available derivatives of OxP include multichromophore systems,13,14 metal-organic frameworks,15 simple N-substituted compounds,6,7,16, and the corrole analogue, OxC.17 These compounds have variously been exploited for sensing applications,18,19 as photosynthetic model systems,20 and for self-assembly.21 Chromophores, such as OxP, with electronic structures that enable triplet excited states can interact with triplet state ambient dioxygen generating singlet oxygen (1O2).22,23 Although as a reactive oxygen species (ROS), 1O2 is often seen as a hazard, recently it has garnered increasing attention due to several possible applications such as in organic oxidative transformations,24 amelioration of pollutants25 (especially for water purification26) and most importantly in photodynamic therapy (PDT)27 including bacterial inactivation28 or cancer treatment.29 PDT applications are based on the essential restricted oxidative properties of 1O2 due to high reactivity (especially towards organic materials) and its moderate lifetime, so that selective tumor targeting becomes possible. Useful chromophore classes such as the phthalocyanines30,31 have properties appropriate for the relevant applications with novel 1O2-generating molecules now being discovered.32 Activation by two-photon absorption is also available for meso-tetraphenylporphyrin33 and its derivatives.34 New materials are screened and can be assessed for their usefulness by direct comparison with an appropriate reference compound.35 Many of the applications involving 1O2-generating molecules including PDT are required to operate in aqueous media so water-soluble reference materials must be used. Despite this, the estimation of 1O2 quantum yields (ΦΔ) in other largely organic media might also be used to assess the usefulness of novel chromophores such as the relatively hydrophobic OxP derivatives. Several classes of compounds can be used as 1O2-generators including C60 buckminsterfullerenes,36 Rose Bengal analogues,37 phenalenone38 and tris(2,2′-bipyridine)ruthenium(II) salts (Ru(Bipy)3Cl2.39 Here we report 1O2-generation by a series of substituted OxP molecules where we have attempted to identify the key structural features required for the effective operation of the chromophore either as a 1O2 generator in its own right, or for use as a reference material to be used in the assessment of other active materials. For the latter, OxP materials might be useful since they possess an intense absorbance in the visible region where many other relevant dyes absorb. In general, we found that per-N-substituted OxP derivatives are the optimum structural type for efficient 1O2 generation while a variation of the N-substituents can also be used to optimize their activity. ΦΔ =𝐼𝑠𝑎𝑚𝑝𝑙𝑒𝐼𝑟𝑒𝑓×ΦΔ𝑟𝑒𝑓 MATERIALS AND METHODS General. Reagents and dehydrated solvents (in septum-sealed bottles) used for syntheses and spectroscopic measurements were obtained from Tokyo Kasei Chemical Co., Wako Chemical Co. or Aldrich Chemical Co. and were used without further purification. Optical absorption spectra were measured using JASCO V-570 UV/Vis/NIR spectrophotometer. FTIR spectra were obtained from solid samples using a Thermo-Nicolet 760X FTIR spectrophotometer. 1H NMR and proton decoupled 13C NMR spectra were recorded on a JEOL JNM-ECS400 NMR spectrometer respectively at 400 MHz, and 101 MHz. For 1H NMR, tetramethylsilane (δ = 0 ppm) was used as a reference while for 13C NMR spectra the residual solvent peak was used as a reference. Data were processed on Delta version 5.0.5.1 and Always JNM-AL version 6.2. 1H NMR chemical shifts (δ) are reported in ppm relative to TMS for CDCl3 (δ 0.00) or the residual solvent peak for other solvents. 13C NMR chemical shifts (δ) are reported in ppm relative to the solvent reported. Coupling constants (J) are expressed in Hertz (Hz), shift multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), double doublet (dd), multiplet (m) and broad singlet (bs). 1O2 photoluminescence spectra were measured using an InGaAs NIR photodetector (R5509-73, Hamamatsu Photonics, Japan) on a NanoLog Horiba Jovin Yvon spectrofluorometer with a 450-W xenon lamp as an excitation source at room temperature. A right-angle detection method and quartz cuvettes with four optical faces and usable in the UV field were used for emission measurements. Compounds OxP,1 OxP(4BrBn)2,40 OxP(4BrBn)4,40 OxP(Bn)4,6 β-Br8OxP,41 β-Br8OxP(4BrBn)2,41 β-Br8OxP(4BrBn)4,42 OxP(4CO2MeBn)415 were prepared and purified according to literature methods. 1O2 quantum yield measurements. Emission spectra and 1O2 photoluminescence spectra were measured using an NIR photodetector (Hamamatsu Photonics, Japan) on a NanoLog Horiba Jovin Yvon spectrofluorometer with a 450 W xenon lamp as an excitation source at room temperature under ambient conditions (unless otherwise stated). To estimate singlet oxygen quantum yields, the solutions of compounds were absorbance normalized (ca. 0.17–0.19 a.u.) with the reference compound (C60 Buckminsterfullerene43,44, ΦΔ = 1) at the relevant excitation wavelength (500 or 510 nm) in toluene. Quantum yields (ΦΔ) were determined by comparison of the average 1O2 photoluminescence maxima values of the reference (Iref) and compound being studied (Isample) between 1270-1275 nm after background subtraction using the formula: (1) Synthesis. OxP(4NO2Bn)4 A round-bottom flask was charged with 2.00 g (1.77 mmol) of 5,10,15,20-tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin and 710 mg (17.7 mmol) of sodium hydride. The solid reagents were dissolved in 500 mL of acetone and stirred for 15 min. After that, 9.2 g (42.6 mmol) of 4-nitrobenzyl bromide dissolved in 50 mL acetone was added. The mixture was heated under reflux. After 4 h, 9.2 g (86.8 mmol) of Na2CO3 was added and the reaction was heated for an additional 20 h. After cooling down the resulting suspension was filtered through a Büchner funnel and the solid residue was washed with CH2Cl2. The filtrate was collected and rotary evaporated. The solid residue was dissolved in a minimal amount of CH2Cl2 and precipitated with MeOH. The green solid was collected by filtration, washed with MeOH, and vacuum dried. Yield: 2.46 g (83 %). UV/Vis (CH2Cl2): λmax (ε, M-1 cm-1) = 272 (73400), 492 (186000) nm. 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.8 Hz, 8H), 7.20 (s, 8H), 6.80 (d, J = 8.4 Hz, 8H), 6.72 (s, 8H), 4.60 (s, 8H), 1.23 (s, 72H) ppm. 13C NMR (100.5 MHz, CDCl3): δ 185.7, 149.4, 147.8, 144.1, 137.9, 134.9, 130.0, 127.9, 126.8, 124.3, 120.6, 47.9, 35.7, 29.4 ppm. FTIR (ATR): ν = 3111 (w), 3078 (w), 2997 (w), 2954 (s), 2910 (m), 2866 (m), 1711 (w), 1641 (w), 1591 (s, carbonyl C=O stretching), 1522 (s), 1489 (m), 1454 (m), 1402 (w), 1389 (w), 1360 (m), 1344 (s), 1325 (m) 1309 (s), 1257 (m), 1221 (w), 1200 (w), 1176 (w), 1111 (w), 1088 (m), 1043 (m), 1016 (m), 960 (w), 953 (m), 930 (m), 920 (w), 906 (w), 887 (w), 856 (m), 839 (m), 820 (m), 800 (s), 756 (w), 744 (w), 729 (s), 704 (w), 683 (w), 661 (w), 640 (w), 623 (m) cm-1. HRMS: found: 1666.8492, calcd.: 1666.8551. OxP(4NH2Bn)4 A round-bottom flask was charged with 1.00 g (0.60 mmol) of OxP(4NO2Bn)4, 3.00 g (12.5 mmol) of Na2S·9H2O and 300 mg (5.60 mmol) of NH4Cl. The flask was three times evacuated and purged with N2. The reagents were dissolved in 120 mL of N2-bubbled DMF and 4 mL of water. The solution was heated at 80 °C for 4 h. After cooling down, 250 mL of water was added. The solvents were partially evaporated on the rotary evaporator. The precipitated solid was collected by filtration, washed with water, and vacuum-dried. The obtained mixture was separated by column chromatography on silica gel with gradient elution from CH2Cl2 to 96:4 CH2Cl2/acetone mixture. OxP(4NH2Bn)3 and OxP(4NH2Bn)4 were isolated. Yield: 0.58 g (62 %). UV/Vis (CH2Cl2): λmax (ε, M-1 cm-1) = 249 (63800), 276 (42800), 328 (19700), 511 (148000) nm. 1H NMR (400 MHz, CDCl3): δ 7.24 (s, 8H), 6.64 (s, 8H), 6.39–6.46 (m, 16H), 4.34 (s, 8H), 3.57 (s, 8H), 1.25 (s, 72H) ppm. 13C NMR (100.5 MHz, CDCl3): δ 186.1, 147.6, 146.1, 138.7, 133.4, 131.9, 131.6, 127.5, 127.4, 121.1, 114.9, 48.4, 35.5, 29.4 ppm. FTIR (ATR): ν = 3460 (br), 3358 (br), 3233 (br), 3001 (w), 2954 (s), 2913 (m), 2864 (m), 1665 (br), 1650 (w), 1640 (w), 1622 (m), 1589 (s, carbonyl C=O stretching), 1519 (s), 1489 (m), 1454 (m), 1407 (w), 1386 (w), 1376 (w), 1359 (s), 1333 (w), 1311 (br), 1256 (m), 1201 (w), 1177 (m), 1128 (w), 1089 (s), 1041 (m), 1016 (m), 957 (m), 945 (m), 928 (m), 906 (w), 888 (m), 865 (m), 838 (m), 820 (s), 809 (w), 788 (m), 741 (s), 715 (w), 661 (m), 638 (w), 623 (s) cm-1. HRMS (ESI-TOF+): found: 1546.9537, calcd.: 1546.9584. OxP(3,5Br2Bn)4 A round-bottom flask was charged with 5,10,15,20-tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin (0.50 g, 0.45 mmol) and sodium hydride (108 mg, 2.7 mmol). Acetone (50 mL) was added and the mixture was stirred for 15 minutes. 3.5-Dibromobenzyl bromide (2.55 g, 11.5 mmol) dissolved in acetone (15 mL) was then added and the mixture was heated under reflux for 6 h. The reaction mixture was allowed to cool, the solvent was evaporated under reduced pressure and the product was isolated from the residue by column chromatography (SiO2/CH2Cl2). Yield: 495 mg (52 %). UV/Vis (CH2Cl2): λmax (ε, M-1 cm-1) = 272 (26900), 325 (21300), 493 (137000) nm. 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 1.6 Hz, 4H), 7.25, (s, 8H), 6.76 (d, J = 1.6 Hz, 8H), 6.73 (s, 8H), 4.35 (s, 8H), 1.28 (s, 72H) ppm. 13C NMR (100.5 MHz, CDCl3): δ 185.9, 149.4, 140.4, 137.3, 134.8, 134.1, 129.9, 128.2, 123.5, 120.6, 47.4, 35.7, 29.4 ppm. FTIR (ATR): ν = 3184 (w), 3118 (w), 2953 (s), 2914 (m), 2865 (m), 1639 (w), 1597 (s), 1558 (m), 1526 (m), 1488 (m), 1454 (m), 1425 (m), 1402 (w), 1388 (w), 1360 (s), 1323 (m), 1308 (s), 1257 (m), 1232 (w), 1221 (w), 1198 (m), 1087 (s), 1042 (m), 1017 (m), 992 (w), 654 (m), 930 (m), 919 (w), 886 (m), 855 (m), 839 (s), 813 (s), 799 (s), 753 (m), 734 (s), 716 (m), 704 (m), 692 (w), 674 (m), 664 (m), 626 (s), 608 (w) cm-1. MALDI-TOF: found: 2116.376, calcd.: 2117.179. OxP(F5Bn)4 A round-bottom flask was charged with OxP (0.83 g, 0.74 mmol), potassium carbonate (2.03 g, 14.7 mmol), and acetone (80 mL). Pentafluorobenzyl bromide (1.55 g, 5.9 mmol) dissolved in acetone (20 mL) was then added and the mixture was heated under reflux. After 2 h, another portion of potassium carbonate (2.03 g, 14.7 mmol) was added. After 20 h of refluxing, the reaction mixture was allowed to cool, the reaction mixture was filtered through a Büchner funnel and the filtrate was evaporated under reduced pressure. The solid residue was dissolved in CH2Cl2 (50 mL) and the insoluble part (mainly the dialkylated product) was filtered off. The product was isolated by column chromatography on SiO2 eluting with CH2Cl2. Yield: 140 mg (10 %). UV/Vis (CH2Cl2): λmax (ε, M-1 cm-1) = 249 (63800), 276 (42800), 328 (19700), 490 (190000) nm. 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 8H), 6.58 (s, 8H), 4.67 (s, 8H), 1.26 (s, 72H) ppm. 13C NMR (100.5 MHz, CDCl3): δ 186.0, 149.3, 137.6, 135.3, 130.2, 127.8, 120.7, 39.6, 35.7, 29.3 ppm. 19F NMR (376.3 MHz, CDCl3): δ -144.7 (d, J = 17.3, 2F), -151.9 (t, J = 21.8, 1F), -160.2 (t, J = 18.8, 2F) ppm. FTIR (ATR): ν = 3188 (w), 2957 (s), 2913 (m), 2867 (m), 1656 (w), 1642 (w), 1601 (s), 1522 (s), 1501 (s), 1456 (w), 1426 (w), 1405 (w), 1380 (w), 1361 (s), 1333 (m), 1318 (s), 1303 (m), 1255 (m), 1229 (w), 1200 (w), 1176 (w), 1140 (w), 1121 (s), 1088 (m), 1043 (m), 1001 (s), 946 (s), 931 (m), 906 (m), 887 (w), 879 (w), 863 (m), 838 (w), 820 (m), 807 (m), 793 (s), 743 (w), 722 (s), 688 (w), 676 (w), 661 (m), 626 (s), 602 cm-1. HRMS (ESI-TOF+): found: 2119.1855, calcd.: 2119.1940. OxP(4TPABn)4 A round-bottom flask was charged with OxP(4BrBn)4 (700 mg, 0.39 mmol), PdCl2(dppf)‧CH2Cl2 (637 mg, 0.78 mmol), 4-(N,N-diphenylamino)phenylboronic acid (1.12 g, 3.87 mmol) and K2CO3 (259 mg, 1.87 mmol). The flask was purged three times with N2. The reactants were dissolved in a degassed mixture of 1,4-dioxane/water (6:1 v/v). The reaction mixture was heated under N2 at 100 °C for 24 h. After allowing the reaction to cool to room temperature, solvents were removed by rotary evaporation, then the solid residue was dissolved in CH2Cl2 and filtered. The solvent was evaporated from the resulting filtrate under reduced pressure and the product was isolated by column chromatography (SiO2/CH2Cl2) and recrystallized from CH2Cl2/hexane mixture. Yield: 520 mg (54 %). UV/Vis (CH2Cl2): λmax (ε, M-1 cm-1) = 334 (121000), 505 (149000) nm. 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 8.0 Hz, 8H), 7.31–7.22 (m, 32H), 7.09–7.00 (m, 32H), 6.74–6.72 (m, 16H), 4.58 (s, 8H), 1.22 (s, 72H) ppm. 13C NMR (100.5 MHz, CDCl3): δ 186.0, 148.0, 147.7, 147.6, 140.6, 138.7, 136.0, 133.9, 133.6, 131.6, 130.7, 129.4, 127.6, 126.9, 126.6, 124.6, 123.7, 123.2, 121.2, 48.6, 35.5, 29.4 ppm. FTIR (ATR): ν = 3182 (w), 3061 (w), 3032 (w), 2999 (w), 2953 (s), 2912 (m), 2883 (w), 2864 (m), 1591 (s), 1525 (m), 1487 (s), 1454 (m), 1404 (w), 1387 (w), 1373 (w), 1360 (s), 1323 (w), 1311 (s), 1290 (w), 1273 (s), 1257 (s), 1194 (w), 1178 (w), 1155 (w), 1115 (w), 1088 (m), 1039 (m), 1016 (m), 1005 (w), 957 (m), 949 (w), 928 (m), 920 (w), 906 (w), 887 (m), 864 (m), 835 (m), 818 (w), 806 (s), 791 (m), 750 (s), 731 (w), 717 (w), 692 (s), 681 (w), 661 (m), 644 (w), 634 (w), 621 (s) cm-1. HRMS (ESI-TOF+): found: 2458.3240 ([M + H]+), calcd.: 2458.3261. OxP(4MeOTPABn)4 A round-bottom flask was charged with OxP(4BrBn)4 (250 mg, 0.14 mmol), PdCl2(dppf)‧CH2Cl2 (225 mg, 0.28 mmol), 4-(N,N-bis(4-methoxyphenyl)amino)phenylboronic acid (485 mg, 1.39 mmol) and K2CO3 (93 mg, 0.67 mmol). The flask was purged three times with N2. The reactants were dissolved in a degassed mixture of 1,4-dioxane/water (6:1 v/v). The reaction mixture was heated under N2 at 100 °C for 24 h. After allowing the reaction to cool to room temperature, solvents were removed by rotary evaporation, then the solid residue was dissolved in CH2Cl2 and filtered. The solvent was evaporated from the resulting filtrate under reduced pressure and the product was isolated by column chromatography (SiO2/CH2Cl2) and recrystallized from CH2Cl2/hexane mixture. Yield: 94 mg (25 %). UV/Vis (CH2Cl2): λmax (ε, M-1 cm-1) = 336 (113000), 505 (143000) nm. 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 8H), 7.29 (s, 8H), 7.23 (d, J = 8.0 Hz, 8H), 7.04 (d, J = 9.2 Hz, 16H), 6.90 (d, J = 8.4 Hz, 8H), 6.81 (d, J = 9.2 Hz, 16H), 6.72 (s, 8H), 6.70 (d, J = 8.0 Hz, 8H), 4.56 (s, 8H), 3.78 (s, 24H), 1.22 (s, 72H) ppm. 13C NMR (100.5 MHz, CDCl3): δ 186.0, 156.1, 148.6, 148.0, 140.7, 138.6, 135.6, 133.9, 131.6, 130.8, 127.4, 126.8, 126.7, 126.5, 121.1, 120.5, 114.8, 55.6, 35.5, 29.4 ppm. FTIR (ATR): ν = 3178 (w), 3110 (w), 3101 (w), 3035 (w), 2997 (w), 2953 (s), 2906 (m), 2866 (w), 2833 (m), 1639 (w), 1593 (s), 1527 (m), 1495 (s), 1454 (m), 1441 (w), 1404 (w), 1387 (w), 1371 (w), 1360 (s), 1313 (s), 1282 (w), 1238 (s), 1194 (w), 1178 (m), 1167 (w), 1105 (w), 1088 (m), 1036 (s), 1016 (m), 957 (m), 947 (w), 930 (w), 922 (w), 906 (w), 887 (w), 864 (w), 825 (s), 808 (s), 756 (m), 744 (w), 719 (m), 669 (w), 640 (w), 623 (m) cm-1. HRMS (ESI-TOF+): found: 1348.7023 ([M]2+), calcd.: 1348.7011. RESULTS AND DISCUSSION The chemical structures of the OxP derivatives used in this work are shown in Chart 1. OxP can be substituted with different groups by N-substitution at pyrrole nitrogen atoms and/or modifications at the pyrrole β-position, although the latter is limited here to persubstitution with bromine. Variation of multiplicity and identity of N-substituent on OxP was investigated for its effect on the efficiency of 1O2 generation in solution. The effect of β-perbromination and N-substituent multiplicity of OxP was assessed only for the 4-bromobenzyl substituent (Chart 1). In this case, for a direct comparison of quantum yields of 1O2 generation of the compounds studied, we have selected toluene as the solvent for this study due to the excellent solubility of all the compounds in that solvent (Br8OxP compounds exhibit only limited solubility in chlorinated solvents and toluene has been used also to avoid any effects due aggregation). For this reason, we have selected C60 fullerene as a reference material for the determination of relative 1O2 quantum yield due to its suitable solubility in toluene and unity 1O2 quantum yield (ΦΔ = 1) at all points where it absorbs in its electronic absorption spectrum.43,44 X-ray crystal structures of several of the compounds are available from previous works and are shown in Fig. 1. N-substitution of OxP occurs without altering the saddle geometry with double N-substitution at N21, N23 occurring on the same face of the molecule and tetra-N-substitution at alternating faces for N21, N22, N23 and N24, as shown in Fig. 2. A key parameter in discussing the structures of these compounds is the dihedral angle subtended between the macrocyclic average plane and the planes of the pyrrole rings, which is 48° for all pyrrole rings in OxP (Fig. 1a). N-substitution increases this angle to around 65° in OxPBn2 for the N-benzyl pyrrole groups (Fig 1b). Buckling of the macrocycle upon per-N-substitution apparently allows a reduction in the corresponding angle in OxPBn4 to 53° (Fig. 1c), although crystal packing forces probably affect macrocyclic puckering since the (4BrBn)4 derivative (Fig. 1d) exhibits a less distorted structure. Per-β-bromination increases the angle subtended by the N-benzyl groups in β-Br8OxP(4BrBn)2 to 72° and in β-Br8OxP(4BrBn)4 to 65°, which is responsible for the blue shift in the absorption maxima of these compounds. For compounds that have not been studied X-ray crystallographically, selected energy-minimized structures are shown in Fig. 2. OxP(3,5Br2Bn)4 (Fig 2a), OxP(F5Bn)4 (Fig. 2b) and OxP(4TPABn)4 (Fig. 2c) are elaborated at the N-benzyl substituents without substantially changing the form of the OxPBn4 unit. Electronic absorption (UV-vis) spectra of selected compounds are shown in Fig. 3. Fig. 3a shows UV-vis spectra of OxP, OxP(4BrBn)2 and OxP(4BrBn)4 indicating the absorption maximum around 500 nm (general for most simple OxP compounds). OxP has an absorption maximum at 518 nm with a tail which extends across the visible range into the near infrared region. The broadness of its spectrum has been attributed to delocalization and tautomeric processes,1 which are obstructed in the N-alkylated derivatives OxP(4BrBn)2 and OxP(4BrBn)4 leading to a narrowing of the absorption band around 510 nm and a small hypsochromic shift (to 504 nm for OxP(4BrBn)4). Bromination of the OxP macrocyclic beta positions leads to more substantial hypsochromic shifts (~30 nm) in the absorption maxima of β-Br8OxP (to 487 nm), β-Br8OxP(4BrBn)2 (509 to 487 nm) and Br8OxP(4BrBn)4 (504 to 472 nm), which is due to increased macrocyclic puckered and a reduction in electronic conjugation (see Fig. 3b). Thus, bromination has a similar effect to N-alkylation presumably because both these modifications lead to reductions in conformational flexibility of the tetrapyrrole core and increased macrocycle distortion. Notably, β-Br8OxP has no absorption tail into the near infrared region and its N-alkylation leads only to small hypsochromic shifts in the OxP absorption maximum (Fig. 3b). In tetra-N-alkylated derivatives of OxP (see Fig. 3c), the presence of electron-withdrawing or electron-accepting groups appears to lead to weak bathochromic or hypsochromic shifts of the absorption maximum, respectively. For example, OxPBn4(4NO2Bn)4 shifts the maximum by 14 nm to 485 nm while OxPBn4(4NH2Bn)4 shifts it by 8 nm to 506 nm. In the spectrum of OxP(4TPABn)4 (green line in Fig. 3c), the large absorption around 320 nm is characteristic of the triphenylamine chromophore. Quantum yields of 1O2 generation (ΦΔ) were estimated by measuring the intensity of 1O2 photoluminescence from solutions of the compounds under irradiation relative to that of C60 in toluene. We have considered the effects of (a) N-substituent multiplicity, (b) β-perbromination/N-substituent multiplicity, and (c) N-substituent identity in OxPBn4 type compounds. Fig. 4 shows spectroscopic data obtained from compounds of different N-substituent multiplicities, i.e., 0, 2 or 4 4-bromobenzyl groups. Fig. 4a shows absorption spectra of the sample solutions normalized at the corresponding irradiation wavelength (510 nm) used for 1O2 generation. Fig. 4b shows 1O2 photoluminescence spectra of the same solutions under irradiation indicating that N-substitution increases the relative 1O2 yield in the order OxP < OxP(4BrBn)2 < OxP(4BrBn)4. This data reveals a substantial increase in yield for the tetra-N-substituted compound. Non-N-substituted OxP appears to generate 1O2 only weakly. The weak 1O2 generating activity observed here for OxP is probably actually due to the presence of the corresponding free base porphyrin TDtBHPP, which has a modest absorbance in the visible range around 520 nm. The fluorescence spectrum of the solution containing OxP (Fig. 4c) contains peaks around 650 and 720 nm, which are characteristic of the presence of the corresponding free base porphyrin. OxP is unstable against reduction in solution and samples left standing to acquire a significant porphyrin content even in the solid state. This may be due to photo-induced water oxidation reaction and, in this case, can be promoted by irradiation of the OxP solution.1 N-alkylation of OxP prevents reduction processes back to the porphyrin so that fluorescence spectra of OxP(4BrBn)2 and OxP(4BrBn)4 contain contributions only from the OxP chromophore. Quantum yields of singlet oxygen generation of the compounds are shown in Table 1. OxP(4BrBn)4 has a large ΦΔ of 0.75, which is competitive with other chromophores used in the relevant applications of PDT and bacterial inactivation.
In previous work, we have also reported the synthesis, isolation and structures of N-alkylated per-β-brominated OxP derivatives β-Br8OxP, β-Br8OxP(4BrBn)241 and β-Br8OxP(4BrBn)4.42 Fig. 5 shows spectroscopic data relevant to the 1O2 generation properties of these compounds. Fig. 5a shows the absorption spectra of the compounds normalized at the irradiation wavelength (500 nm). β-Octabromination leads to a blue shift of ~25-30 nm in the OxP absorption maximum due to inductive effects due to the bromo-substituents.41 Fig. 5b shows the 1O2 response at 1275 nm and again indicates an increase in quantum yield on increasing N-alkylation. Br8OxP exhibits a high ΦΔ compared to OxP while N-alkylation nearly doubles this value for both of the N-alkylates (see Table 2). Interestingly, the fluorescence emission from the compounds is effectively quenched by increasing N-alkylation, which could be an effect of the increasing 1O2 quantum yield being exhibited as a decrease in emission intensity due to the change in the mode of excitation energy loss from radiative towards the energy transfer to atmospheric oxygen via the triplet excited state. These data indicate that Br8OxP derivatives, even the parent compound, are capable of generating singlet oxygen at a useful level.
Based on data obtained for the OxP and Br8OxP families of compounds, it appears that the tetra-N-alkylated OxP compounds represent the optimized form of the chromophore for 1O2 generation. Therefore, we have studied the available tetra-N-benzylated compounds. Fig. 6 shows spectroscopic data used to estimate the ΦΔ values of these compounds. ΦΔ data is summarized in Table 3 where compounds are listed according to their increasing ΦΔ values. Several observations can be made about the data including that electron-donating groups such as amino or 4-methoxyTPA are detrimental to the value of ΦΔ while electron-withdrawing groups are present in compounds with larger ΦΔ. A well-known method to improve ΦΔ of 1O2 generating chromophores is to replace hydrogen atoms bonded to the chromophore with heavy atoms such as bromine or iodine (the so-called heavy atom effect).45 In this case, this effect does not hold well for the per-β-brominated OxP derivatives β-Br8OxP, β-Br8OxP(4BrBn)2 and β-Br8OxP(4BrBn)4 although modest improvements in ΦΔ were found. The effect is most pronounced for compounds with increasingly high halogen substitution culminating in the perfluorobenzyl derivative OxP(F5Bn)4. It is presently unclear whether the non-N-substituted OxP chromophore is capable of photosensitizing singlet oxygen. Its poor or lack of activity might be due to the availability of other routes of relaxation by conformational variation of the saddle macrocycle or even tautomeric processes.1,17 This is supported circumstantially by the structure of the β-Br8OxP derivative where multiple β-bromine atoms obstruct macrocyclic processes, rigidifying the chromophore. While β-Br8OxP is likely of lower macrocyclic flexibility, it still contains multiple NH groups, which appear detrimental to 1O2 generation in OxP derivatives based on the data in Tables 1 & 2. However, it is not possible easily to separate these effects from other heavy atom effects due to the presence of multiple Br atoms. The most important feature to note is that β-Br8OxP(4BrBn)4 has an ΦΔ inferior to the non-Br derivative suggesting that perbromination at the tetrapyrrole macrocycle is not beneficial for 1O2 generation in the optimal tetra-N-substituted OxPBn4 compounds. In those compounds, it is possible to consider the effects of N-benzyl substituent substituents, including those of electron-donating vs electron withdrawing and multiplicity of halogen atoms. Basically, free amine groups have a strong negative effect on ΦΔ while other groups having electron-donating groups are also not favored. This is most likely due to photo-induced electron transfer between electron rich N-substituents and electron deficient OxP chromophore, which is known to be a significant property in similar compounds,13,14,20 and results in quenching of the excited states required for singlet oxygen generation. Multiple halogen atom substitution at the N-benzyl group (as opposed to β-substitution) leads to the highest so far observed values of ΦΔ for OxP compounds. Finally, OxPBn4(4NO2Bn)4 and OxPBn4(4CO2MeBn)4 also exhibit ΦΔ values around 0.75 indicating that electron-withdrawing groups can also promote the efficiency of 1O2 photosensitization in N-substituted OxP compounds. OxPBn4 has only recently emerged as an effective 1O2 photosensitizer. It is an important addition to this class of compounds because of its synthetic flexibility, strong absorption in the visible region (see Fig. 6c) and high stability under irradiation (see Fig. 6d). The OxPBn4 class of compounds is complementary to the existing compound types such as meso-tetraphenylporphyrins/chlorins (TPP,46 TPC47), Rose Bengal derivatives,37 phenalenones38 fuchsonarenes,48 and fullerenes,36 amongst others.49,50 Each of these families of compounds has its own benefits and also disadvantages. For instance, 1O2 photosensitizer activity of porphyrins can be quenched due to aggregation in particular media while fullerene derivatives can also suffer the effects of aggregation or poor solubility, as well as being deactivated for 1O2 generation in aqueous media due for various reasons. Molecular design of appropriate OxPBn4 derivatives can be used to eliminate these disadvantages in the corresponding compounds providing a useful alternative to the existing materials. Whilst the extinction coefficients of OxP derivatives are typically lower than porphyrins, their broad absorption profiles over a large section of the visible region means that a broader range of excitation sources can be used. They also offer the potential for a larger photon absorption density and comparable stabilities to the currently used classes of chromophores. The non-planarity of the OxP system gives access to 3-dimensional scaffolds that are not traditionally obtainable utilizing planar chromophores, which have already proven useful in the preparation of porous coordination polymers.15 Finally, in this work we have identified several key features of OxP derivatives important for optimizing their singlet oxygen generating capabilities. This has also revealed some unusual features of the compounds including certain perhaps counterintuitive properties. These include the fact of the property optimization based on variation in structure of non-conjugated N-benzyl substituents, and fluorescence quenching according to increasing N-substitution in the β-Br8OxP series. For the former, it is likely that the sterically crowded nature of the OxPBn4 derivatives promotes the influence even of non-conjugated N-substituents either by inductive or through space effects. Fluorescence quenching according to increasing N-substitution in the β-Br8OxP series is more difficult to account for but might be due to reductions in conjugative overlap between moieties of the OxP chromophore resulting in inaccessible excited states. CONCLUSIONS To summarize, we have established some of the design rules to optimize the molecular structures of 1O2 photosensitizers based on the OxP chromophore. These are: (1) tetra-N-substitution is the optimal form of OxP compound; (2) bromination of the OxP chromophore improves ΦΔ but not in the OxPBn4 compounds; (3) electron-withdrawing groups (nitro, ester) on the N-benzyl groups promote ΦΔ; (4) increased multiplicity of halogen substitution at the N-benzyl substituents optimizes ΦΔ with perfluorobenzyl groups so far providing the best characteristics, OxP(F5Bn)4. The synthetic possibilities of the OxP system suggest developments of materials for this application in various directions, and we will report advances in the preparation of OxP-based 1O2 photosensitizers in due course. In particular, the addition of water-solubilizing groups such as ethylene glycol chains might provide materials for use in aqueous systems similar to that found for TPP-type compounds.51 Acknowledgements D.T.P is grateful to the National Institute for Materials Science, International Center for Young Scientists, Japan (ICYS, NIMS) for an ICYS fellowship and research funds. J.H. is grateful to the Japan Society for the Promotion of Science (JSPS) for a JSPS Fellowship. FD is grateful for support by the US National Science Foundation. This research was partly supported by World Premier International Research Center Initiative (WPI Initiative), MEXT, Japan. REFERENCES 1. Milgrom LR. Tetrahedron 1983; 39: 3895–3898. 2. Milgrom LR, Flitter WD, Short EL. J. Chem. Soc., Chem. Commun. 1991; 788–790. 3. Milgrom LR, Flitter WD. Tetrahedron 1992; 48: 2951–2956. 4. Evans TA, Srivatsa GS, Sawyer, DT, Traylor TG. Inorg. Chem. 1985; 24: 4733–4735. 5. Traylor TG, Nolan KB, Hildreth R, Evans TA. J. 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Colors of the structures reflect the approximate hues of solutions of the relevant compounds in chlorinated solvents (non-N-substituted-OxP: dark purple; di-N-substituted-OxP: mauve; tetra-N-substituted-OxP: red, etc.). Abbreviations of the compounds are given for ease of reference in the text. Fig. 1. Single crystal X-ray structures of (a) OxP,8 (b) OxPBn2,6 (c) OxPBn4,6 (d) OxP(4BrBn)4,40 (e) β-Br8OxP(4BrBn)2,41 (f) β-Br8OxP(4BrBn)4.42 Fig. 2. Structures of (a) OxP(3,5Br2Bn)4, (b) OxP(F5Bn)4, (c) OxP(4TPABn)4 computed at the MM2 level using the ChemDraw3D program. Fig. 3. Electronic absorption spectra of selected OxP compounds. (a) OxP (blue line), OxP(4BrBn)2 (black line) and OxP(4BrBn)4 (red line). (b) β-Br8OxP (black line), β-Br8OxP(4BrBn)2 (light green line) and β-Br8OxP(4BrBn)4 (pink line). (c) OxP(4NH2Bn)4 (black line), OxP(4NO2Bn)4 (blue line), OxP(3,5Br2Bn)4 (dark green dashed line) and OxP(4TPABn)4 (light green line). 450 500 550 600 650 700 7500.00.10.20.3Absorbance (a.u.)Wavelength (nm) C60 OxP OxP(4BrBn)2 OxP(4BrBn)4 1225 1250 1275 1300 1325010002000300040005000Intensity (cps)Wavelength (nm) C60 OxP OxP(4BrBn)2 OxP(4BrBn)4 600 800 1000 12000102030405060Intensity (x103 cps)Wavelength (nm) C60 OxP OxP(4BrBn)2 OxP(4BrBn)4 Fig. 4. Electronic absorption and photoluminescence spectra for OxP, OxP(4BrBn)2 and OxP(4BrBn)4. (a) UV-vis spectra of solutions of the compounds and reference (C60) having approximately equivalent absorbances at the wavelength of irradiation (510 nm) in toluene. (b) 1O2 photoluminescence spectra of the solutions under irradiation. (c) Steady state fluorescence emission spectra of the solutions. (a) (b) (c) 450 500 550 600 650 700 7500.000.050.100.150.200.250.300.350.40Absorbance (a.u.)Wavelength (nm) C60 β-Br8OxP β-Br8OxP(4BrBn)2 β-Br8OxP(4BrBn)4 1225 1250 1275 1300 13250500100015002000Intensity (cps)Wavelength (nm) C60 β-Br8OxP β-Br8OxP(4BrBn)2 β-Br8OxP(4BrBn)4 Fig. 5. Electronic absorption and photoluminescence spectra for β-Br8OxP, β-Br8OxP(4BrBn)2 and β-Br8OxP(4BrBn)4. (a) UV-vis spectra of solutions of the compounds and reference (C60) having approximately equivalent absorbances at the wavelength of irradiation (500 nm) in toluene. (b) 1O2 photoluminescence spectra of the solutions under irradiation. (b) (a) 450 500 550 600 650 700 7500.00.10.20.30.4Absorbance (a.u.)Wavelength (nm) C60 OxPBn4 OxP(4BrBn)4 OxP(3,5Br2Bn)4 OxP(4TPABn)4 OxP(4MeOTPABn)4 OxP(F5Bn)4 OxP(4CO2MeBn)4 OxP(4NO2Bn)4 OxP(4NH2Bn)41225 1250 1275 1300 1325 1350010002000300040005000Intensity (cps)Wavelength (nm) C60 OxPBn4 OxP(4BrBn)4 OxP(3,5Br2Bn)4 OxP(4TPABn)4 OxP(4MeOTPABn)4 OxP(F5Bn)4 OxP(4CO2MeBn)4 OxP(4NO2Bn)4 OxP(4NH2Bn)4 300 350 400 450 500 550 600 650 700010002000300040005000Intensity @ 1270 nm (cps)Excitation Wavelength (nm) C60 OxP(3,5Br2Bn)4 OxP(F5Bn)40 10 20 30 40 50 600200040006000800010000Intensity (cps)Time (Min) OxP(4BrBn)4 OxP(F5Bn)4 Fig. 6. Electronic absorption and photoluminescence spectra for OxPBn4, OxP(4BrBn)4, OxP(3,5Br2Bn)4, OxP(4TPABn)4, OxP(4MeOTPABn)4, OxP(F5Bn)4, OxP(4CO2MeBn)4, OxP(4NO2Bn)4 and OxP(4NH2Bn)4. (a) UV-vis spectra of solutions of the compounds and reference (C60) having approximately equivalent absorbances at the wavelength of irradiation (510 nm) in toluene. (b) 1O2 photoluminescence spectra of the solutions under irradiation. (c) 1O2 excitation spectra of solutions of the indicated compounds under irradiation with monitoring at 1270 nm (d) Chromophore stability profiles of solutions of the indicated compounds under irradiation at 510 nm monitoring at 1270 nm in toluene. (a) (b) (c) (d) Table 1. Variation of ΦΔ with increasing N-substitution of OxP. Table 2. Variation of ΦΔ with increasing N-substitution of β-Br8OxP. Table 3. N-substituent dependency of ΦΔ for OxPBn4 arranged in order of increasing quantum yield. Compound Emission Intensity @ 1270-1275 nm (c.p.s.) ( ΦΔ) OxP 143 0.04 OxP(4BrBn)2 735 0.19 OxP(4BrBn)4 2878 0.75 C60 (ref.)43,44 3849 1 Compound Emission Intensity @ 1270-1275 nm (c.p.s.) ( ΦΔ) β-Br8OxP 425 0.31 β-Br8OxP(4BrBn)2 687 0.51 β-Br8OxP(4BrBn)4 748 0.55 C60 (ref.)43,44 1358 1 Compound λmax (nm) Emission Intensity @ 1270-1275 nm (c.p.s.) ( ΦΔ) OxP(4NH2Bn)4 506 879 0.24 OxP(4MeOTPABn)4 500 1193 0.33 OxPBn4 498 2121 0.58 OxP(4TPABn)4 500 2266 0.62 OxP(4CO2MeBn)4 493 2701 0.74 OxP(4NO2Bn)4 485 2770 0.76 OxP(4BrBn)4 494 2829 0.77 OxP(3,5Br2Bn)4 488 2800 0.77 OxP(F5Bn)4 485 2981 0.82 C60 (ref.)43,44 540 3657 1