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7Порфирины_ МаКрОГ8Т8рОЦМКЛЬ1_Статья
Porphyrins http://macroheterocycles.isuct.ru Paper
DOI: 10.6060/mhc2011.4.05
Regioselective Nitration of 5-Phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine
Alexey Lyubimtsev,@ Sergey Syrbu, Natal'ya Zheglova, Alexandr Semeikin, and Oscar Koifman
Dedicated to Professor Michael Hanack on the occasion of his 80th Anniversary
Ivanovo State University of Chemistry and Technology, Ivanovo 153000, Russia @ Corresponding author E-mail: [email protected]
Nitration system NaNO-TFA for regioselective nitration of the meso-positions of 5-phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (1) was examined. The degree of nitration is easily controlled by the amount ofNaNO2 used and by the reaction time. All compounds are characterized by MS, UV-Vis-, and 1H NMR-spectroscopy as well as mass-spectrometry. Protonation of transannular protons of some synthesized porphyrins is discussed.
Keywords: Porphyrin, nitration, meso-mtroporphyrins, trifluoroacetic acid, sodium nitrite.
Introduction
Porphyrins (Ps), due to their peculiar electronic and redox properties, play a key role in many living nature processes such as oxygen activation and transfer, electron transfer, binding or transport of small molecules, light harvesting and photosynthesis.[1]
Chemical modification of natural and synthetic porphyrins has been an area of interest for a number of years. Development of new methodologies to functionalize Ps and their derivatives can provide a variety of novel compounds that otherwise could only be obtained by a total synthesis. Several investigations have shown that porphyrins and their metal complexes undergo electrophilic substitution reactions (nitration, formylation, deuteration and methylation)
[2] as well as radical reactions (halogenations and oxidation)
[3] in a similar manner like simple aromatic systems. Nitro-porphyrins have proved to be versatile starting materials for the synthesis of porphyrins with other functionalities.[4] In addition, the number and position of introduced into the porphyrin core nitro-groups can influence dramatically on the acid-base properties of porphyrins and control the NH-tautomerism processes.
Here we present the synthesis of meso-mononitro- (2a, 2b), meso-dinitro- (3a, 3b) and meso-trinitro- (4) porphyrins by nitration of 5-phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (1) using NaNO2/trifluoroacetic acid (TFA) system, where the degree of nitration could be easily controlled by the reagents ratio (Scheme 1).
Experimental
Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Analytical TLC was performed on Kieselgel F-254-percolated TLC plates. For flash chromatography, silica gel 60 (230 - 400 mesh)
was used. 1H NMR spectra were recorded on Bruker AC 250 and 400 spectrometers. The UV-visible spectra were taken in benzene with a Lambda 25 UV-visible spectrometer. Mass spectra were obtained on a Finnigan TSQ 70 MAT spectrometer.
5-Phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (1) was obtained as described earlier.1[5] MS (EI) m/z: 526.2 (100) [M]+. 1H NMR (CDCl3) 5 ppm: 10.14 (s, 2H, H-20), 9.94 (s, 1H, H-15), 8.08-7.99 (m, 2H, H-Ph), 7.83-7.66 (m, 3H, H-Ph), 4.10 -4.01 (m, 4H, -CH2-), 3.62 (s, 6H, -CH3), 3.51 (s, 6H, -CH3), 2.43 (s, 6H, -CH3), 1.87 (t, J = 7.50 Hz, 6H, -CH3(Et)), -3.21 (br, 2H, NH). UV-Vis (C6H6) Xmax nm (log s): 405 (5.22), 502 (4.15), 534 (3.86), 573 (3,83), 626 (351).
5-Phenyl-10-nitro-2,3, 7,8,12,18-hexamethyl-13,17-diethylporphine (2a) and 5-phenyl-15-nitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2b). To a solution of 1 (105 mg, 0.2 mmol) in TFA (10 ml) was added sodium nitrite (13 mg, 0.19 mmol). After 10 min stirring at room temperature, the reaction mixture was quenched with ice water (50 ml) and neutralized with aqueous ammonia. Precipitate was filtrated and dried in vacuum. The resulting mixture of porphyrins was separated by column chromatography on silica gel, using chloroform as eluent. First zone was characterized as 5-phenyl-15-nitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2b) and second major zone - as 5-phenyl-10-nitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2a). Only traces of starting porphyrin 1 were separated as last zone.
5-Phenyl-10-nitro-2,3, 7,8,12,18-hexamethyl-13,17-diethylporphine (2a). Yield: 76 mg (66%). MS (EI) m/z: 571.2 (68) [M]+, 525.2 (100) [M-NO2]+. 1H NMR (CDCl3) 5 ppm: 9.98 (s, 1H, H-20), 9.89 (s, 1H, H-15), 8.04-7.94 (m, 2H, H-Ph), 7.84-7.64 (m, 3H, H-Ph), 4.09 - 3.82 (m, 4H, -CH2-), 3.51 (s, 3H, -CH3), 3.38 (s, 3H, -CH3), 3.27 (s, 3H, -CH3), 3.15 (s, 3H, -CH3), 2.29 (s, 3H, -CH3), 2.26 (s, 3H, -CH3), 1.85 - 1.75 (m, 6H, -CH3(Et)), -3.54 (s, 2H, NH). UV-Vis (C6H6) Xmax nm (lg s): 405 (5.06), 508 (4.09), 538 (3.78), 581 (3.76), 633 3 (3.48).
5-Phenyl-15-nitro-2,3, 7,8,12,18-hexamethyl-13,17-diethylporphine (2b). Yield: 27 mg (24%). MS (EI) m/z: 571.2 (100) [M]+, 526.3 (44) [M-NO2]+. 1H NMR (CDCl3) 5 ppm: 10.23 (s, 2H, H-20), 7.99 - 7.96 (m, 2H, H-Ph), 7.83 - 7.66 (m, 3H, H-Ph), 3.73 - 3.64 (m, 4H, -CH2-), 3.60 (s, 6H, -CH3), 3.47 (s, 6H, -CH3), 2.41
(s, 6H, -CH3), 1.65 (t, J = 7.50 Hz, 6H, -CH3(Et)), -2.73 (s, 1H, NH), -3.15 (s, 1H, NH). UV-Vis (C6H6) Xmax nm (lg s): 405 (5.07), 507 (4.08), 540 (3.78), 576 (3.76), 630 (3"56), 658 (3.27).
Mixture of 5-phenyl-10,20-dinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (3a) and 5-phenyl-10,15-dinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (3b). Method A. To a solution of 1 (105 mg, 0.2 mmol) in TFA (10 ml) was added sodium nitrite (28 mg, 0.4 mmol). After 1.5 h stirring at room temperature, the reaction mixture was quenched with ice water (50 ml) and neutralized with aqueous ammonia. Precipitate was filtrated and dried in vacuum. Column chromatography on silica gel with chloroform as eluent gives mixture no separable dinitroporphyrins 3a and 3b. Yield: 102 mg (83%). MS (EI) m/z: 616.2 (64) [M]+, 571.3 (100) [M-NO2]+, 525.3 (100) [M-2NOJ+. 'H NMR (CDCl3) 5 ppm: 9.94 (s, 1H), 9.77 (s, 1H), 8.06 - 8.02 (m, 2H, H-Ph), 7.97 -7.93 (m, 2H, H-Ph), 7.85 - 7.66 (m, 6H, H-Ph), 3.89 - 3.79 (m, 4H, -CH2-), 3.60 - 3.51 (m, 4H, -CH2-), 3.43 (s, 3H, -CH3), 3.27 (s, 3H, -CH3), 3.17 (s, 3H, -CH3), 3.15 (s, 6H, -CH3), 3.00 (s, 3H, -CH3), 2.98 (s, 6H, -CH3), 2.21 (s, 3H, -CH3), 2.19 (s, 3H, -CH3), 2.07 (s, 6H, -CH3), 1.72 (t, J = 7.50 Hz, 6H, -CH3(Et)), 1.60 - 1.51 (m, 6H, -CH3(Et)), -3.06 (s, 1H, NH), -3.26 (s, 2H, NH), -3.36 (s, 1H, NH). Method B. To a solution of 2a (57 mg, 0.1 mmol) in TFA (5 ml) was added sodium nitrite (10 mg, 0.15 mmol). After 1.5 h stirring at room temperature, the reaction mixture was quenched with ice water (25 ml) and neutralized with aqueous ammonia. Precipitate was filtrated and dried in vacuum. Column chromatography on silica gel with chloroform as eluent gives mixture no separable dinitroporphyrins 3a and 3b. MS and UV-Vis data were similar to the data given in Method A. 'H NMR (CDCl3) 5 ppm: 10.00 (s, 0.5H, H-20), 9.80 (s, 1H, H-15), 8.05 (d, J = 8 Hz, 2H, H-Ph), 7.98 (d, J = 8 Hz, 1H, H-Ph), 7.84 - 7.71 (m, 4.5H, H-Ph), 3.94 - 3.80 (m, 4H, -CH2-), 3.60 - 3.51 (m, 2H, -CH2-), 3.46 (s, 1.5H, -CH3), 3.31 (s, 1.5H, -CH3), 3.16 (s, 7.5H, -CH3), 2.99 (s, 1.5H, -CH3), 2.97 (s, 6H, -CH3), 2.24 (s, 1.5H, -CH3), 2.20 (s, 1.5H, -CH3), 2.0 7 (s, 6H, -CH3), 1.72 (t, J = 6.04 Hz, 6H, -CH3(Et)), 1.54 - 1.49 (m, 3H, -CH3(Et)), -3.06 (s, 0.5H, NH), -3.27 (s, 2H, NH), -3.36 (s, 0.5
H, NH). 3
5-Phenyl-10,15-dinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (3b). To a solution of 2b (57 mg, 0.1 mmol) in TFA (5 ml) sodium nitrite (10 mg, 0.15 mmol) was added. After
I.5 h stirring at room temperature, the reaction mixture was quenched with ice water (25 ml) and neutralized with aqueous ammonia. Precipitate was filtrated and dried in vacuum. Column chromatography on silica gel with chloroform as eluent gives porphyrin 3b. Yield: 56 mg (91%). MS (EI) m/z: 571.3 (100) [M-NO2]+, 526.3 (95) [M-2NOJ+. 'H NMR (CDCl3) 5 ppm: 10.00 (s, 1H, H-20), 8.02 - 7.94 (m, 2H, H-Ph), 7.81 - 7.69 (m, 3H, H-Ph), 3.63 - 3.49 (m, 4H, -CH2-), 3.46 (s, 3H, -CH3), 3.32 (s, 3H, -CH3), 3.16 (s, 3H, -CH3), 3.00 (s, 3H, -CH3), 2.25 (s, 3H, -CH3), 2.20 (s, 3H, -CH3), 1.62 - 1.45 (m, 6H, -CH3(Et)), -3.03 (s, 1H, NH), -3.34 (s, 1H, NH). UV-Vis (C6H6) Xmax nm (lg s): 410 (5.04), 508 (4.07), 540 (3.92), 579 (3.89), 630 (3.57).
5-Phenyl-10,15,20-trinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (4). To a solution of 1 (53 mg, 0.1 mmol) in TFA (5 ml) sodium nitrite (69 mg, 1.0 mmol) was added. After 2 days stirring at room temperature, the reaction mixture was quenched with ice water (100 ml) and neutralized with aqueous ammonia. Precipitate was filtrated and dried in vacuum. Column chromatography on silica gel with chloroform as eluent gives porphyrin 4. Yield: 52 mg (78 %). MS (EI) m/z: 662.4 (35) [M]+, 647.4 (100) [M-CH3]+. 'H NMR (CDCl3) 5 ppm: 8.11 - 8.01 (m, 2H, H-Ph), 7.85 - 7.74 (m, 3H, H-Ph), 343 - 3.27 (m, 4H, -CH2-), 2.97 (s, 3H, -CH3), 2.80 (s, 3H, -CH3), 1.98 (s, 3H, -CH3), 1.38 (t, J = 7.50 Hz, 6H, -CH3(Et)), -2.45 - -3.24 (m, 2H, NH). UV-Vis (C6H6) Xmax nm (lg s): 433 (4.77), 532 (3.94), 609 (3.65), 679 (3.44). ""
The same product was obtained by reaction of mixture 3a and 3b with excess of sodium nitrite in TFA for 2 days at room temperature.
Results and Discussion
Synthesis
Nitration of porphyrin 1 could be carried out using different nitrating systems such as nitric acid or acetyl nitrate in acetic acid, nitric acid in dichloromethane, sodium nitrate in TFA as well as sodium nitrite in TFA, all leading to the same products. However, the best yields were achieved with the latter system. Thus, reaction of 1 with 0.95 equivalents of NaNO2 in TFA leads in 15 min to a mixture of two mono-nitrated products 2a and 2b in 3:1 ratio (Scheme 1), which were separated by column chromatography on silica gel using chloroform as eluent. The ratio of isomers differs from the statistically expected due to the steric hindrance of attack in position 15 of the porphyrin core.
Increase of the NaNO2 amount up to 2 equivalents to porphyrin 1 allows to obtain a mixture of meso-dinitroporphyrins 3a and 3b in an approximately 1:1 ratio, when conducting the reaction for 1.5 h.
Unfortunately, the mixture could not be separated by column chromatography. The mixture of the same products in 2:1 ratio was also formed upon nitration of 5-phenyl-10 -nitro -2,3,7,8,12,18 -hexamethyl-13,17 -diethylporphin (2a) with 1.5 molar excess of NaNO2. Nevertheless, pure 5-phenyl-10,15-dinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphin (3b) could be prepared by nitration of 2b using 1.5 equivalents of NaNO2, thus allowing a reliable assignment of signals in the 'H NMR spectrum of 3a and 3b products mixture.
Both porphyrin 1 and the mixture of porphyrins 3a and 3b give 5-phenyl-10,15,20-trinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphin (4) upon nitration with 10 equivalents of NaNO2 for 2 days. Neither longer reaction time (up to 8 days) nor increase of the reaction temperature to 70 °C lead to nitration of phenyl ring in 1, thus excluding the formation of tetranitro derivative.
UV-Vis and MS Spectra
The UV-Vis spectra of mono-nitroporphyrins 2a and 2b (Figure 1) in benzene are very similar with the spectrum of 1. The only observed difference is a slight bathochromic shift of all absorption bands and a negligible decrease of their intensity for the nitrated species compared to the initial porphyrin.
Figure 1. UV-Vis spectra of porphyrins 1, 2a and 2b in benzene. Макрогетероциmbl /Macroheterocycles 2011 4(4) 265-269
3a
3b
Scheme 1. Nitration of 5-phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (1) with NaNO2-TFA: i - 0.95 equv. NaNO2, 15 min, r.t.; ii - 2.0 equv. NaNO2, 2 h, r.t.; iii - 1.5 equv. NaNO2, 2 h, r.t.; iv - 10.0 equv. NaNO2, 2 d, r.t. (see experimental part for details).
Presence of two nitro-groups in positions 10 and 15 of dinitro-derivative 3b do not change the spectral pattern compared to the mono-nitro products 2a and 2b, whereas trinitroporphyrin 4 features a three-band spectrum in the visible region with all bands including Soret-band being pronouncedly red-shifted (Figure 2).
Figure 2. UV-Vis spectra (benzene) of porphyrins 3b and 4.
Mass-spectra of all synthesized nitro-porphyrins display the peak of corresponding molecular ion as well as the fragmentation peaks, which are mainly due to the loss of nitro-groups.
H NMR Spectra
Signals of three meso-protons in the 'H NMR spectrum (Figure 3) of porphyrin 1 in CDCl3 appear as two singlets at 10.14 (2H-20) and 9.94 (H-15) ppm. Five protons of phenyl ring give two multiplets in the range of 8.08 - 7.66 ppm. Three singlets at 3.62, 3.51 and 2.43 ppm correspond to 18 protons of p-methyl groups, whereas a multiplet at 4 ppm and a triplet at 1.87 ppm are due to four and six protons respectively of the ethyl substituents. Resonances of two transannular imine protons appear as a broad singlet at -3.21 ppm.
Interestingly, in an acidic deuterated chloroform due to the traces of HCl or DCl a subset of low intensity peaks arises. These peaks are shifted either down or high field compared to the main signals of the above described pattern, maintaining their multiplicity. In the high field area of the spectrum, however, two new sharp signals appear at -0.90 and -1.95 ppm in addition to the broad singlet (Figure 3 a). This new set of signals was ascribed to a double-protonated form of 1 considering the integration values and the number of imine proton resonances.
A threefold dilution of the porphyrin solution in CDCl3 increases the fraction of the protonated species from ca. 10% to 30%, suggesting a large equilibrium constant of the protonation (Figure 3b). The signals of protonated form
Figure 3. 1H NMR spectra of 5-phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (1): a - in CDCl3; b - in CDCl3 after dilution; c - in CDCl3 with two drops DEA; d - in pyridine-d5.
Figure 4. 'H NMR spectra (CDCl3) 5-phenyl-10-nitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2a) and 5-phenyl-15-nitro -2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2b).
disappear upon addition of strong base like diethylamine (Figure 3c) as well as when deuterated pyridine or THF is used as a solvent for the 'H-NMR-experiments (Figure 3d). Moreover, the broad signal of imine protons of 1 split in this case into two resolved singlets with good matching in integration, which is consistent with the symmetry of the macrocyclic tautomer of lowest energy depicted in Scheme 1. Obviously, the broadening of imine resonance in CDCl3 is caused by a relatively fast tautomerism, being catalyzed by the traces of acid. Such feature was also noticed previously for a range of other mono-phenylporphyrins.[5]
'H NMR spectra of mono-nitro derivatives 2a and 2b are also very characteristic. Thus, 2b having a C2v-symmetric core
exhibits only one signal of meso-protons (positions 10 and 20) at 10.23 ppm, whereas in the spectrum of C-symmetric 2a two singlets (meso-protons in positions 15 and 20) are observed in this region (Figure 4). The lowered symmetry of 2a due to the nitro-group in position 10 is also a reason for the non-equivalence of p-methyl as well as p-ethyl groups in the 1H NMR spectrum. In the case of porphyrin 2b, the signals pattern of p-methyl and p-ethyl protons remains as that of 1.
In the high field two imine protons of 5-phenyl-10-nitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2a) appear as a singlet at -3.54 ppm, splitting into two signals at lower temperature (Figure 4). Similar behavior was observed also for the imine protons of 1 and is to assign to a high
tautomerism rate at room temperature, which decreases upon cooling down. In the case of 2b the imine protons give two singlets at -3.15 and -2.73 ppm as is also to expect from the symmetry of the macrocycle. The shape and position of these signals are temperature independent in the range of 313-233 K. This indicates a relatively slow tautomerism even at room temperature due to the higher energy barrier between different tautomeric forms caused by a strong polarizing effect of phenyl and nitro substituents situated opposite to each other in the porphyrin macrocycle. Additionally, the change of acid-base properties of 2b compared to 1 can also influence the dynamics of tautomers interconversion. To be precise, introduction of nitro-groups into mono-phenylporphyrin decreases the basicity of the pyrrolic A-atoms, since only traces of the corresponding protonation products were observed in the 'H NMR spectra recorded in acidic CDCl3.
Conclusions
Selective nitration of 5-phenyl-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (1) was carried out using sodium nitrite/trifluoroacetic acid system. Depending on the reagents ratios and reaction time the following porphyrins could be obtained either as individual compounds or as mixtures: 5-phenyl-10-nitro-2,3,7,8,12,18-hexamethyl-13, 17-diethylporphine (2a), 5-phenyl-15-nitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (2b), 5-phenyl-10,15-dinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (3b), 5-phenyl-10,20-dinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (3a) and 5-phenyl-10,15,20-trinitro-2,3,7,8,12,18-hexamethyl-13,17-diethylporphine (4). Formation of tetranitro derivative using this reaction protocol is prohibited: neither high excess of sodium nitrite nor increasing the reaction time and temperature lead to such product. As found from 'H NMR experiments, nitration of porphyrin 1 decreases the basicity of pyrrolidinic nitrogen atoms of the porphyrin moiety.
Acknowledgements. This work was carried out under
financial support of Russian Foundation for Basic Research
(project N 02.740.11.0106).
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Received 21.08.2011 Accepted 13.10.2011
