Synthesis of C-Functionalized Chloro- / Nitro- Tetra-

phenylporphyrin Derivatives – Polysubstituted

in meso-Aryl Rings

Stanisław Ostrowski^a,b) and Agnieszka Mikus^a)

(a) Institute of Chemistry, University of Podlasie, ul. 3 Maja 54, 08-110 Siedlce, Poland

(b) Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52,

01-224 Warszawa, Poland

Abstract: Nitration of 5,10,15,20-tetrakis(3-chlorophenyl)porphyrin with fuming yellow nitric acid at room temperature leads to a mixture of four polynitrated compounds, in which 5,10-bis(3-chloro-4-nitrophenyl)-15,20-(3-chlorophenyl)porphyrin and 5,10,15-tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)porphyrin were the major products. The above trinitro-porphyrin reacts, in the presence of t-BuOK at 0°C, with carbanions of ClCH₂SO₂Tol, BrCH₂SO₂Tol, and ClCH₂SO₂NMe₂ to give products of the nucleophilic substitution of hydrogen in the meso-nitroaryl rings. By this route, the preparation of the ”synthetic” porphyrins (bearing up to ten Cl-, N-, and C-substituents) is performed.

Key words: 5,10,15,20-Tetrakis(3-chlorophenyl)porphyrin, and its Derivatives; Nitration; Carbanions; Nucleophilic Substitution of Hydrogen.

Many of porphyrin derivatives are of significant importance due to their potential use as photosensitizers in Photodynamic Therapy (PDT),¹⁾ molecular-based multi-bit memory storage,²⁾ electron-donor parts in artificial photosynthetic models,³⁾ etc.. Their precursors can be obtained by the selective functionalization of the easily available (in one-step cyclocondensation) ”synthetic” tetraphenylporphyrin,⁴⁾ or its derivatives. From this process the hydrophobic moieties can be transformed into the lipophilic compounds, which being soluble in physiological milieu may be considered, for example, as potential PDT agents.

We present herein a method for the synthesis of highly substituted 5,10,15,20-tetraarylporphyrins (mono-, di-, and tri-), in one or more of the meso-aryl rings, by the tandem electrophilic nitration / nucleophilic substitution of hydrogen reactions. The electrophilic nitration of meso-tetraarylporphyrins may lead to mono-substitution in the para-position of one of the meso-aryl rings. This was observed for first time by Kruper et al.,⁵⁾ and similar results were obtained by other laboratories.⁶⁾ The NO₂ group is one of the most versatile substituents for further transformations. Recently, we also published a paper concerning the selective nitration of meso-tetraarylporphyrins in two neighbouring aromatic rings.⁷⁾ And now, we found that the exhaustive nitration of 5,10,15,20-tetrakis(3-chlorophenyl)porphyrin allows the preparation of higher nitro-substituted products (tri- or even tetranitro- derivatives) with moderate yields.

The above polynitration could be realized with the use of fuming yellow nitric acid (d = 1.53, Fluka), at room temperature, with large amounts of the acid. In this reaction, the desired 5,10,15-tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)-porphyrin (2) was obtained in a reasonable yield (25%). Nevertheless, all the possible products were isolated and identified in this case (also mono-, di-, or even small amounts of tetranitro- derivative). The preparation of the above 5,10,15-tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)-porphyrin (2) is impossible to realize effectively by the alternative Rothemund and Adler-Longo cross-condensation⁸⁾or by the synthesis via dipyrromethanes methodology.⁹⁾

Scheme 1

We published some papers in the recent past concerning the nucleophilic functionalization of mono-nitroaryl-substituted porphyrin zinc complexes.^6d,6e) Subsequently we proved that this nucleophilic reaction [the so-called vicarious nucleophilic substitution (VNS)¹⁰⁾] can be also realized for unprotected porphyrins.¹¹⁾ Thus, the attempts of the nucleophilic substitution of hydrogen in unprotected 5,10,15-tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)-porphyrin (2) were undertaken herein to prepare porphyrins possessing high degree of complexity. We found that the reaction of 2 with carbanion of ClCH₂SO₂Tol (3a), in t-BuOK/DMF system at 0°C, leads to a complicated mixture of three products: two inseparable disubstituted compounds (4 and 5; total yield 15%), and 6 (yield 24%). The disubstituted products 4/5 were identified by MS [only molecular ion m/z = 1222 (M+H) by the ESI method was detected] and confirmed by ¹H NMR investigations (a broad signal originating from several diverse CH₃-Tol groups was observed at ca 2.40 ppm). However, in this case, the formation of considerable amounts of the product substituted in all of the meso-nitroaryl rings (6; yield 24%) was observed. In the similar process of 2 with sulphonamide 3b (with a prolonged reaction time) only one product was formed in high yield (7; 68%) – an unexpected outcome.

The differentiation of the above reaction courses is not clear - possibly the bulkiness of the carbanion generated from ClCH₂SO₂Tol is crucial for this process, thus causing considerable steric hindrances when the carbanion approaches the porphyrin. This could be also a case of a leaving group. Indeed, in the reaction of 2 with bromomethyl para-tolyl sulphone (3c), bearing an excellent leaving group (–Br), the yield was relatively higher to give mainly the trisubstituted product 6 (47%), accompanied with small amounts of the mixture of 4 and 5.

Probably, the both above factors operate; however, in the latter case an every attack of carbanion moiety could be the effective one – because the next step of the VNS reaction¹⁰⁾(an elimination of HBr) is easier process as compared to elimination of HCl.

Scheme 2

The ability to access new types of porphyrin derivatives is of great importance due to the biological activity of these systems. In this paper, we presented the methodology for the functionalization of 5,10,15,20-tetrakis(3-chlorophenyl)porphyrin by tandem electrophilic/nucleophilic reactions in this system. The introduction, in a controlled process, of many Cl-, N-, and C-substituents into the meso-aryl moieties, was demonstrated to give compounds bearing up to ten functional groups.

Experimental

¹H NMR spectra were recorded with a Varian GEMINI-200 spectrometer operating at 200 MHz. Coupling constants J are expressed in hertz [Hz]. Mass spectra were measured with an AMD 604 (AMD Intectra GmbH, Germany) spectrometer (LSIMS method) and MARINER (ESI-TOF) PerSeptive Biosystems spectrometer (ESI method); m/z intensity values for peaks are given as a % of relative intensity. UV-VIS spectra were measured with Beckman DU-68 spectrometer. TLC analysis was performed on aluminium foil plates pre-coated with silica gel (60F 254, Merck). Silica gel, 200-300 mesh and 230-400 mesh (Merck AG), was used for column chromatography.

The tetrachloro-porphyrin derivative used and the starting carbanion precursors, were obtained according to methods described in earlier literature: 5,10,15,20-tetrakis(3-chlorophenyl)porphyrin (1),^4,7) chloromethyl para-tolyl sulphone (3a),¹²⁾ N,N-dimethyl-(chloromethane)sulphonamide (3b),¹³⁾ bromomethyl para-tolyl sulphone (3c).¹⁴⁾

Selected Procedures:

5,10,15-Tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)porphyrin (2). – To 5,10,15,20-(3-chlorophenyl)porphyrin (1; 51 mg, 0.068 mmole) 1.5 g of nitric acid (ca 1.0 mL; d = 1.53) was added at room temperature and stirred for 4 min. Then, CHCl₃ (10 mL) was added and it was poured onto ice water (30 mL). The organic layer was separated and washed with water (5 x 10 mL). After drying over MgSO₄/Na₂CO₃ and evaporation of the solvent the crude residue was chromatographed (CHCl₃/n-hexane; from 1:1 to 4:1, then with CHCl₃) to give the starting 5,10,15,20-(3-chlorophenyl)porphyrin – 6 mg (12%), 5-(3-chloro-4-nitrophenyl)-10,15,20-tris(3-chlorophenyl)porphyrin – 12 mg (22%), 5,10-bis(3-chloro-4-nitrophenyl)-15,20-bis(3-chlorophenyl)porphyrin – 15 mg (26%), 5,10,15-tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)porphyrin (2) – 25 mg (25%), and 5,10,15,20-tetrakis(3-chloro-4-nitrophenyl)porphyrin – 1.5 mg (2%).

Data for 5-(3-chloro-4-nitrophenyl)-10,15,20-tris(3-chlorophenyl)porphyrin and 5,10-bis(3-chloro-4-nitrophenyl)-15,20-bis(3-chlorophenyl)porphyrin – see lit.⁷⁾

Data for Product 2: – m.p. > 300°C. – ¹H NMR (CDCl₃, 200 MHz): 8.94 (d, J = 5.0 Hz, 2 H, H^b-pyrrole), 8.89-8.78 (m, 6 H, H^b-pyrrole), 8.42 (s, 3 H, H-2 of H-Ar(Cl)(NO₂)), 8.34 (part of AB, J = 8.2 Hz, 3 H, H-5 of H-Ar(Cl)(NO₂)), 8.30-8.18 (m, 4 H, H-Ar), 8.10 (apparent d, J = 7.2 Hz, 1 H, H-4 of Ar-Cl), 7.84-7.68 (m, 2 H, H-5 and H-6 of Ar-Cl), -2.90 (broad s, 2 H, 2xNH). – UV-VIS (CHCl₃), l_max (lge) [nm]: 645 (3.26), 590 (3.70), 556.5 (3.75), 516 (4.15), 421.5 (5.36, Soret). – LSIMS (+), m/z (% rel. int.): 893 (0.7), 892 (2), 891 (2), 890 (4), 889 (5), 888 (8), 887 (5), 886 (5), 885 (3) [isotopic M⁺ and M+H]; – HR-LSIMS (+) calcd. for C₄₄H₂₃N₇O₆³⁵Cl₃³⁷Cl (M⁺) – 887.0434, found – 887.0358.

Reaction of Porphyrin 2 with ClCH₂SO₂NMe₂ (3b). – To a stirred solution of t-BuOK (26 mg, 0.24 mmol) in anhydrous DMF (3 mL, under argon), a solution of 5,10,15-tris(3-chloro-4-nitrophenyl)-20-(3-chlorophenyl)porphyrin (2; 30 mg, 0.034 mmol) and N,N-dimethyl-(chloromethane)sulphonamide (3b, 21 mg, 0.133 mmol) in DMF (1 mL) was added dropwise via syringe at 0°C during ca 10 min. After an additional 2.5 h of stirring at this temperature the mixture was poured into 3% HCl containing ice (40 mL). The precipitate was filtered, washed with water, and then dissolved in CHCl₃ (40 mL). After drying with anhydrous MgSO₄ and evaporation of the solvent, the residue was chromatographed (eluent: CHCl₃/n-hexane, 2:1), to give pure 7, 29 mg (68%).

– M.p. > 300°C. – ¹H NMR (CDCl₃): 9.00-8.85 (m, 8 H, H^β-pyrrole), 8.56-8.35, 8.29-7.98, and 7.90-7.64 (3 x m, 10 H, H-Ar), 4.55 (s, 6 H, 3xCH₂), 3.04-2.93 (m, 18 H, 3xN(CH₃)₂), -2.95 (broad s, 2 H, 2xNH). – UV-VIS (CHCl₃), λ_max [nm]: 643.5 (3.97), 590.5 (4.12), 555.5 (4.16), 515 (4.42), 422.5 (5.54, Soret). – MS (ESI), m/z (% rel. int.): 1257 (3), 1256 (5), 1255 (14), 1254 (25), 1253 (59), 1252 (52), 1251 (100), 1250 (27), and 1249 (45) [isotopic M+H]; – HR-MS (ESI) calcd. for C₅₃H₄₅N₁₀O₁₂Cl₄S₃ (M+H) – 1249.1135, found – 1249.1152.

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