7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003

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[A002]

Introduction of Carbon Substituents into Nitro- and Dinitro- meso-Tetraarylporphyrins by Vicarious Nucleophilic Substitution of Hydrogen

Stanisław Ostrowski,^a,b) Agnieszka Mikus,^a) Agnieszka Borkowska^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: meso-Tetraphenylporphyrin derivatives in the reaction with fuming yellow nitric acid form 5-(4-nitroaryl)-10,15,20-triarylporphyrins or 5,10-bis(4-nitroaryl)-15,20-diarylporphyrins – depending on the reaction conditions. The above nitroporphyrins react, in the presence of a base (t-BuOK) at 0°C, with carbanions (which bear nucleophugal groups at the carbanionic center: ClCH₂SO₂Tol and ClCH₂SO₂NMe₂) leading to the nucleophilic substitution of hydrogen in one or two of the meso-nitroaryl rings. By this route, the introduction of carbon substituents into the tetraarylporphyrins was demonstrated.

Key words: meso-Tetraphenylporphyrin Derivatives, Nitration, Carbanions, Vicarious Nucleophilic Substitution of Hydrogen.

The porphyrin system is present in many well-known biological materials (e.g. chlorophyll, heme, vitamin B₁₂).¹⁾ The important porphyrin precursors (especially those of higher lipophilicity) are usually isolated from naturally occurring substances and transformed into compounds possessing high degree of complexity. On the other hand, a similar effect can be achieved by the selective functionalization of the easily available (in one-step cyclocondensation) ”synthetic” tetraphenylporphyrin,²⁾ or its derivatives. From this process the hydrophobic moieties can be also transformed into the lipophilic compounds.

We present herein a method for the selective derivatization of meso-tetraarylporphyrins, leading to highly substituted derivatives (mono-, di-, and tri-) in one or more of the meso-aryl rings. By this method, the synthesis of the meso-tetraarylporphyrins bearing O-, N-, or C-substituents was demonstrated. Usually, the first substituent (Cl, OCH₃, and CH₃) was introduced to the system due to cyclocondensation of pyrrole with the respective substituted aromatic aldehydes. Introduction of the next group (NO₂ in this case) was achieved by the direct electrophilic nitration of the system. The nitro group, which lends the possibility for the subsequent transformation to other nitrogen functionality (reduction to NO and NH₂, further functionalization via diazotisation, substitution of hydrogen in position ortho-,³⁾ many types of cyclizations,⁴⁾ etc.), is one of the most versatile substituents for this purpose.

Nitration. The electrophilic nitration of meso-tetraarylporphyrins may lead to mono-substitution in the para-position of one of the meso-aryl rings (e.g. compound 2). This was observed for first time by Kruper et al.,⁵⁾ and similar results were obtained by other groups⁶⁾ (also in our laboratory^3c,3d). In a case of 5-(3-methoxy-4-nitrophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin (2), which was used for further functionalization in this work, we obtained as a major product the desired compound (34%), accompanied with dinitrated moiety, 5,10-bis(3-methoxy-4-nitrophenyl)-15,20-bis(3-methoxyphenyl)porphyrin (3b, 11%). On the other hand, the selective nitration of meso-tetraarylporphyrins may lead to dinitrated products in two neighbouring aromatic rings⁷⁾ (e.g., compounds 3a,b). The nitro-porphyrins synthesised were used for further functionalization.

Scheme 1

Substitution of Hydrogen in Nitro-substituted meso-Tetraarylporphyrins. We published some papers in the recent past concerning the nucleophilic functionalization of mono-nitroaryl-substituted porphyrin zinc complexes.^3c,3d,8) Subsequently we proved that this nucleophilic reaction (particularly the vicarious nucleophilic substitution^3b)) can be also realized for unprotected porphyrins.⁹⁾ We have now combined our observations concerning nitration (dinitration) and nucleophilic substitution with the possibility of preparing the corresponding highly substituted porphyrins. Carbanions generated from chloromethyl para-tolyl sulphone (4) and from N,N-dimethyl chloromethanesulphonamide (6) (standard nucleophiles for the VNS process) were selected for these reactions. Compounds 4 and 6 were the carbanion precursors of choice, because they allow the synthesis of porphyrin derivatives containing sulphur (VI) substituents. These types of precursors may lead to moieties which could have potential bioactive properties (prior research has revealed several sulphonyl TPP derivatives to have anti-cancer activity¹⁰⁾). On the other hand, as an electrophilic partners, mono- and dinitrated meso-tetraarylporphyrins (2 and 3a,b) were used.

The nucleophilic substitution of hydrogen in unprotected mono-nitrated porphyrin, demonstrated herein for more complicated model – 5-(3-methoxy-4-nitrophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin (2) (in the reaction with 4), leads to the desired product 5, however with moderate yield (Scheme 2, 15%).

Scheme 2

The same reaction in porphyrins dinitrated in two neighbouring meso-aryl rings [5,10-bis(4-nitrophenyl)- and 5,10-bis(3-methoxy-4-nitrophenyl)- porphyrins, 3a and 3b] allows the possibility for synthesis of tetrasubstituted or even octasubstituted systems in fully-controlled transformations. Thus, in the reaction of 3a with N,N-dimethyl chloromethanesulphonamide (6), if performed in the presence of t-BuOK in DMF at 0°C, the substitution takes place mainly in two nitrophenyl rings to give compound 8a as a major product in moderate yield (29%); accompanied by the mono-substituted derivative 7a (yield 15%). Analogously, in the reaction of dinitroporphyrin 3b with chloromethyl para-tolyl sulphone (4), in the same reaction conditions, a mixture of compounds 7b (16%) and 8b (14%) was obtained.

Scheme 3

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 meso-tetraaryl porphyrins by tandem electrophilic/nucleophilic reactions in these systems. The introduction, in a controlled process, of many functional groups (up to 8) into the meso-aryl moieties, was possible. The preparation of the above products is impossible to realize effectively by the alternative methods. These compounds could be of higher lipophilicity (or could be a precursors for such derivatives); hence may be of potential use as the photosensitizers in photodynamic therapy.¹¹⁾

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 (electron impact and LSIMS methods) 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.

Some nitroporphyrins used and the starting carbanion precursors, were obtained according to methods described in earlier literature: 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin (3a),⁷⁾ 5,10-bis(3-methoxy-4-nitrophenyl)-15,20-bis(3-methoxyphenyl)porphyrin (3b),⁷⁾ chloromethyl para-tolyl sulphone (4),¹²⁾ N,N-dimethyl-(chloromethane)sulphonamide (6).¹³⁾

Nitric acid (d = 1.53) – from Fluka.

Selected Procedures:

5-(3-Methoxy-4-nitrophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin (2). – meso-Tetrakis(3-methoxyphenyl)porphyrin (50 mg, 0.068 mmole) was dissolved in dry CHCl₃ (10 mL), and the solution was stirred under argon and cooled to ca 0-2°C. To this mixture nitric acid (310 mg, 0.2 mL, d = 1.53) was added via syringe. After 15 min. the next portion of HNO₃ (0.2 mL) was added and the reaction was continued for 0.5 h (TLC monitoring). The reaction mixture was washed with water (2 x 50 mL) and dried with MgSO₄/Na₂CO₃. After evaporating the solvent, the crude residue was chromatographed using a mixture of n-hexane/CHCl₃ as eluent (1:5) to give: 5-(3-methoxy-4-nitrophenyl)-10,15,20-tris(3-methoxyphenyl)porphyrin (2) – 18 mg (34%) and 5,10-bis(3-methoxy-4-nitrophenyl)-15,20-bis(3-methoxyphenyl)porphyrin (3b) – 6 mg (11%; for data see lit.⁷⁾).

Compound 2 was earlier mentioned in the literature,⁵⁾ however it was not isolated in a pure form, as well as – not characterized.

(2): – m.p. >300°C. – ¹H NMR (CDCl₃, 200 MHz): 8.94 (d, J = 4.9 Hz, 2 H, H^b-pyrrole), 8.91 (s, 4 H, H^b-pyrrole), 8.82 (d, J = 4.9 Hz, 2 H, H^b-pyrrole), 8.29 (d, J = 8.2 Hz, 1 H, H-5 of Ar(OCH₃)(NO₂)), 7.98 (d, J = 1.5 Hz, 1 H, H-2 of Ar(OCH₃)(NO₂)), 7.94 (dd, J = 8.2,1.5 Hz, 1 H, H-6 of Ar(OCH₃)(NO₂)), 7.84-7.14 (m, 12 H, H-Ar), 3.99 (s, 9 H, 3xOCH₃), 3.98 (s, 3 H, OCH₃), -2.81 (broad s, 2 H, 2xNH). – UV-VIS (CHCl₃), l_max [nm]: 645, 589.5, 551, 516, 420 (Soret). – MS (ESI), m/z (% rel. int.): 783 (2), 782 (8), 781 (53), 780 (100) [isotopic M+H], 301 (2); – HR-MS (ESI) calcd. for C₄₈H₃₈N₅O₆ (M+H) – 780.2822, found – 780.2829.

Reactions of Porphyrins 2 and 3b with ClCH₂SO₂Tol (4). – To a stirred solution of t-BuOK (30 mg, 0.27 mmol) in anhydrous DMF (6 mL, under argon), a solution of corresponding methoxyporphyrin (2, 3b; 0.042 mmol) and chloromethyl para-tolyl sulphone (4; 15 mg, 0.073 mmol) in DMF (3 mL) was added dropwise via syringe at 0°C during ca 10 min. After an additional 5 h of stirring at this temperature the mixture was poured into 3% HCl containing ice (100 mL). The precipitate was filtered, washed with water, and then dissolved in CHCl₃ (50 mL). After drying with anhydrous MgSO₄ and evaporation of the solvent, the crude products were purified by column chromatography or by preparative TLC (eluent: CHCl₃/n-hexane, 1:1). The yields of the pure products:

5 – 6 mg, 15% (from 2);

7b – 6.5 mg, 16%; and 8b – 6.6 mg, 14% (from 3b).

Spectral Data for Selected Product 5:

5-[3-Methoxy-4-nitro-5-(toluene-4-sulphonylmethyl)phenyl]-10,15,20-tris(3-methoxy-phenyl)porphyrin (5): – m.p. >300°C. – ¹H NMR (CDCl₃): 9.06-8.88 (m, 8 H, H^β-pyrrole), 8.58-8.52, 8.33-8.20, and 8.00-7.32 (3 x m, 18 H, H-Ar), 4.72 (s, 2 H, CH₂), 4.15-3.98 (four lines, 12 H, 4xOCH₃), 2.36 (s, 3 H, CH₃), -2.89 (s, 2 H, 2xNH). – UV-VIS (CHCl₃), λ_max [nm]: 644.5, 592, 555, 516, 414 (Soret). – MS (ESI), m/z (% rel. int.): 952 (3), 951 (6), 950 (21), 949 (67), and 948 (100) [isotopic M+H], 761 (5), 760 (16), 759 (30), 668 (2), 512 (1), 475 (2), 417 (11), 334 (1), 250 (2), 182 (7); – HR-MS (ESI) calcd. for C₅₆H₄₆N₅O₈S (M+H) – 948.3067, found – 948.3129.

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