Efficient nitration of meso-tetraphenylporphyrin with nitronium tetrafluoroborate

Controllable and selective nitration of meso -tetraphenylporphyrin using nitronium tetrafluoroborate affords a chromatography-free access


Introduction
Porphyrins are a versatile class of compounds with numerous applications in catalysis, biomimetics, photodynamic therapy, non-linear optics and molecular-based storage devices, among many others. 1Facile and versatile selective functionalization of readily available porphyrins will further increase the utility of porphyrins.Synthetic approaches to unsymmetrically functionalized porphyrins rely on either Rothermund or Lindsey's condensations, 2 which are usually multi-step processes that require extensive separation steps.In this light, selective functionalization of easily accessible and commercially available mesotetraphenylporphyrin, TPP, (Figure 1) is highly desirable.
Nitration of TPP to produce nitro-porphyrins is attractive in view of facile conversion of the NO2-group into amino, nitroso and diazonium functionalities en route to elaborate porphyrincontaining scaffolds. 3Notably, porphyrins featuring electron-withdrawing substituents have also been shown to possess interesting and unusual properties.Nitration of porphyrins has been evaluated using a variety of nitrating agents. 5Mononitration of TPP was reported to proceed smoothly with an excess of either red or yellow nitric acid; however, subsequent introduction of additional nitro-groups proved to be less efficient. 6In addition, in the presence of trifluoroacetic acid (TFA)sodium nitrite, TPP was converted into a mixture of bis-nitrophenyl-porphyrins, i.e., 5,10-bis-NO2-TPP and 5,15-bis-NO2-TPP (Figure 1), which was directly subjected to the reduction with SnCl2/acid, followed by a chromatographic separation to afford the corresponding diaminoporphyrins in moderate yields. 7verall, the reported approaches rely on large excess of reagents, and usually lead to mixtures of nitrated products, which require either chromatographic separation or conversion to the corresponding amines, followed by chromatographic separation.Here we report on an efficient and selective preparation of nitro-porphyrins using [NO2]BF4 in sulfolane as a mild, easy to handle and selective nitrating agent.

Results and Discussion
[NO2]BF4 is a known nitrating reagent for various aromatic species. 8However, application of this reagent for nitration of porphyrins has received limited attention.Previous research demonstrated that [NO2]BF4 in sulfolane at elevated temperatures did not readily nitrate porphyrins. 9In pyridine, at high temperatures, [NO2]BF4 mediated the incorporation of a pyridinium moiety onto TPP scaffold. 10n our hands, a complex mixture was obtained when TPP was subjected to an excess of [NO2]BF4 at room temperature, whereas treatment of TPP with 1 equivalent of [NO2]BF4 at room temperature, did not induce any nitration, and TPP was recovered unchanged.However, when [NO2]BF4 was added sequentially, that is, the first equivalent was added drop-wise, the reaction was allowed to stir for several minutes, followed by a drop-wise addition of another equivalent of [NO2]BF4, a clean and quantitative conversion (based on TLC and 1 H NMR analysis of the crude mixture) of TPP to NO2-TPP was obtained (Scheme 1).
Encouraged by these results, we decided to explore the ability of [NO2]BF4 to produce a series of nitro substituted TPP analogues.This sequential addition of [NO2]BF4 proved essential for a controlled, selective introduction of the nitro-functionality into the porphyrin, and bis-and tris-nitrated TPP products were obtained in high yields (Scheme 1).Importantly, dinitration of TPP using [NO2]BF4 yielded exclusively 5,10-bis-NO2-TPP (Figure 1).Furthermore, subjecting NO2-TPP and 5,10-bis-NO2-TPP to a sequential addition of [NO2]BF4 produced 5,10-bis-NO2-TPP and 5,10,15-tris-NO2-TPP, respectively, as judged by TLC monitoring.Regretfully, our attempts to produce 5,10,15,20-tetrakis-NO2-TPP (Figure 1) using TPP as the starting material failed as a complex mixture of products was obtained.In this light, we explored the nitration of 5,10,15-tris-NO2-TPP. Sequential addition of [NO2]BF4 of up to 6 equivalents to a dichloromethane solution of 5,10,15-tris-NO2-TPP did not result in the desired nitration product and unreacted starting material was recovered.Upon further increase of the amount of [NO2]BF4 (up to 10 equivalents) we observed a formation of a complex mixture of products as determined by TLC and NMR analyses.
As an alternative route to obtain 5,10,15,20-tetrakis-TPP, we probed the effect of various additives on the nitration of TPP with [NO2]BF4.Nitration of porphyrins in the presence of TFA was shown to be extremely facile. 7Therefore, we probed the ability of TFA/[NO2]BF4 system to aid in the formation of 5,10,15,20-tetrakis-NO2-TPP.Addition of equimolar [NO2]BF4 to a mixture of TPP and TFA proved to be highly reactive as mixtures of NO2-TPP, 5,10-bis-NO2-TPP and 5,15-bis-NO2-TPP along with some unreacted TPP were obtained.Our attempts to take advantage of the high reactivity of this system to produce 5,10,15,20-tetrakis-NO2-TPP were unsuccessful, and complex mixtures were obtained once the TPP/TFA mixtures were exposed to an excess of [NO2]BF4.Conducting the reactions at lower temperature as well as using various ratios of TFA/CH2Cl2 as the reaction mixture did not provide any improvement.Furthermore, substituting TFA with a less reactive glacial acetic acid appeared to be much inferior, as primarily unreacted TPP was observed, with small amounts of NO2-TPP and 5,10-bis-NO2-TPP observed by TLC even after the addition of 5 equivalents of [NO2]BF4.
Although nitration of TPP using [NO2]BF4 in sulfolane is attractive, removal of sulfolane presented a concern.For small-scale reactions (ca.50 mg of TPP) a flash chromatography (CH2Cl2/silica gel) was found to be convenient in removing sulfolane.However, in case of 5,10,15-tris-NO2-TPP synthesis, as well as large scale (ca.0.9-1.0g of TPP) the amount of sulfolane demanded repetitive chromatographic purification.In this light, we searched for a nonchromatographic approach.It appeared that dissolving a crude mixture, i.e., nitrated TPP and sulfolane, in hot acetone followed by addition of excess of water and subsequent cooling was efficient in yielding pure nitrated porphyrins.Importantly, both isolation protocols provided virtually the same yields, i.e., 82 % for small-scale reactions, which utilized flash chromatography, and 86 % for large-scale reactions, which utilized the precipitation-based procedure.All prepared here nitro-containing TPP (Scheme 1) were successfully reduced to the corresponding amines, following a literature procedure. 7etalloporphyrins, namely Cu-TPP and Zn-TPP, did not undergo nitration under these conditions, and decomposition of the porphyrin's structure was detected even upon addition of 1 equivalent of [NO2]BF4.We also investigated the effect of solvents and solvent mixtures on the [NO2]BF4 nitration of TPP.CH2Cl2 proved to be the only efficient solvent.The use of mixtures of CH2Cl2 and CH3CN or Et2O proved inefficient, as no nitration product was detected, and TPP was recovered unchanged even upon addition of 4 equivalents of [NO2]BF4.
In order to gain some insight on the mechanism of [NO2]BF4 nitration, we examined the effect of the sequential [NO2]BF4 addition to TPP using NMR spectroscopy (Scheme 2).
TPP exhibits a typical singlet at -2.8 ppm, corresponding to two N-Hs, and a set of three resonances in the aromatic region (Scheme 2).Upon addition of 1 equivalent of [NO2]BF4 the NH sharp peak disappeared, and two broader peaks were detected between ca.-1 and -3 ppm, and the aromatic region also underwent a dramatic change as a new set of peaks was noted: TPP's multiplets at 7.8 and 8.2 ppm partially shifted downfield to 8.0 and 8.6 ppm, respectively; whereas the singlet at 8.9 ppm shifted upfield to 8.7 ppm.Notably, a change from a red solution (TPP in dichloromethane) to a green solution upon addition of [NO2]BF4 was observed.This color change is similar to that observed upon protonation of TPP by TFA or any other strong acid.Furthermore, the changes of the aromatic resonances, which were observed upon addition of 1 equivalent of [NO2]BF4 to TPP, were virtually identical to those observed upon addition of 1 equivalent of TFA to TPP.Also, 19 F NMR exhibited a sharp singlet at -156.2 ppm.Both 1 H and 19 F NMR spectra had remained unchanged over a 1.5-hour period.Formation of NO2-TPP was not observed at this stage, as judged by TLC analysis performed during the preparative procedure, which arguably suggested that a mixture of NO2 + -coordinated and free TPP was obtained at this stage.
It should be pointed out that 19 F NMR of a [NO2]BF4-sulfolane solution in CDCl3 (22 mM) showed a broad signal at -150 ppm, whereas a more concentrated solution, i.e., 2.2 M, exhibited a multiplet at ca. -150 ppm and broad multiplet centered around -155 ppm.The ratio between these signals depended on the concentration of the solution.being located in between the porphyrins, which would provide some extra stabilization of the positive charge.
The NMR changes (Scheme 2) were in accordance with TLC monitoring of the preparative reactions, which indicated that all TPP was quantitatively converted into the mononitrated porphyrin.Further monitoring of the [NO2]BF4 addition was precluded by the increasing amounts of sulfolane.However, when nitration of NO2-TPP with [NO2]BF4 was monitored by NMR under identical conditions described for nitration of TPP, we observed qualitatively similar changes of all resonances, both 1 H and 19 F. Overall, the NMR results suggested that the nitration of TPP using [NO2]BF4 proceeded via a nitronium coordinationnitration sequence in a highly controllable manner.

Conclusions
We have identified [NO2]BF4 as a convenient reagent for selective and controllable nitration of TPP under mild conditions.Consecutive incorporation of up to three nitro-groups is readily achieved, and the corresponding nitro-containing porphyrins can be isolated using a chromatography-free procedure in high yields.

Experimental Section
General.All reagents and solvents were from commercial sources (Sigma-Aldrich, Acros or Alfa Aesar) and were used as received.TPP was purchased from Frontier Scientific, Inc.Reactions were monitored by TLC (silica gel 60 F254).Column chromatography was performed using silica gel (230-400 mesh). 1 H NMR spectra were recorded on a Varian (300 MHz) spectrometer.The chemical shifts are reported in ppm () downfield from tetramethylsilane in CDCl3.

Synthesis of NO2-TPP
Solution of TPP (59 mg, 0.096 mmol) in CH2Cl2 (13.5 ml) was purged with N2 for 10 min at room temperature.[NO2]BF4 (0.175 ml, 0.09 mmol; 0.5 M in sulfolane) was added dropwise over a period of 10 min.The mixture was stirred for 30 min, and another portion of [NO2]BF4 (0.175 ml, 0.09 mmol; 0.5 M in sulfolane) was added dropwise.The mixture was stirred for 10 min and water (100 ml) was added.The organic layer was washed with water (2 x 100 ml), dried (MgSO4) and volatiles removed in vacuo.The residue was flash chromatographed using dichloromethane as eluent to give 52 mg (82 % yield) of NO2-TPP, those spectral properties matched the published data.Synthesis of NO2-TPP, a scale-up procedure.Solution of TPP (0.93 g, 1.51 mmol) in CH2Cl2 (180 ml) was purged with N2 for 10 min at room temperature.[NO2]BF4 (2.74 ml, 1.37 mmol; 0.5 M in sulfolane) was added dropwise over a period of 30 min (slow addition was found to be crucial for the mononitration; faster addition rates tended to produce mixtures of NO2-TPP and 5,10-bis-NO2-TPP).The mixture was stirred for 30 min, and another portion of [NO2]BF4 (2.74 ml, 1.37 mmol; 0.5 M in sulfolane) was added dropwise over a period of 30 min.At this time, TLC showed small amount of unreacted TPP, hence [NO2]BF4 (0.5 ml, 0.25 mmol; 0.5 M in sulfolane) was added dropwise over ca. 5 min.The mixture was stirred for 15 min, followed by the dropwise over ca.5min addition of [NO2]BF4 (0.5 ml, 0.25 mmol; 0.5 M in sulfolane) and the mixture was allowed to stir for 20min.TLC indicated a complete consumption of TPP.Next, the reaction mixture was extracted with water (2 x 200 ml), and the volatiles removed in vacuo.The residue was dissolved in acetone (10 ml) and added to ice/water mixture (ca.800 ml).The formed precipitate was collected by filtration, dissolved in CH2Cl2 (ca.50ml), dried (MgSO4) and volatiles removed in vacuo to give 0.94 g (94 % yield) of NO2-TPP.

Synthesis of 5,10-bis-NO2-TPP
Solution TPP (64 mg, 0.10 mmol) in CH2Cl2 (13.5 ml) was purged with N2 for 10 min at room temperature.[NO2]BF4 (0.19 ml, 0.095 mmol; 0.5 M in sulfolane) was added dropwise over a period of 10 min, and stirring continued for 30 min.The addition was repeated in the same manner until a total of 2.9 equivalents of [NO2]BF4 were added.Following the addition of dichloromethane (100 ml) and water (100 ml), the organic layer was washed with water (2 x 100 ml), dried (MgSO4) and volatiles removed in vacuo.The residue was dissolved in acetone (3.0 ml) and water was added until cloudiness (ca.50 ml) was observed.The mixture was placed on ice and the precipitate was collected by filtration to give 65 mg (92 % yield) of 5,10-bis-NO2-TPP, those spectral properties matched the published data.