Synthesis of 5-(4-X-Phenyl)-10,15,20-tris(Substituted Phenyl) Porphyrins Using Dipyrromethanes

Abstract

5-(4-X-Phenyl)-10,15,20-tris(substituted phenyl) porphyrins (4-6) were synthesized from meso-(substituted phenyl) dipyrromethanes (1-3), which in turn were prepared in yields of 75-92 %. This synthetic pathway was compared with the binary mixed aldehyde and pyrrole condensation method. The reported dipyrromethane approach is advantageous for porphyrins substituted by –OCH₃ (4) and -F (6) groups (12-14 %), while the yield of porphyrins bearing –N(CH₃)₂ (5) groups was similar (~0.3 %) by both methods.

Introduction

Meso-substituted porphyrins are the great interest for the development of model systems in biomimetic and materials chemistry [1]. Peripherally asymmetric AB₃-porphyrins, bearing three identical substituted phenyl groups (B), can be covalently linked to other structures by the functional group contained in the remaining phenyl substituent (A) [2,3]. These porphyrins bearing two different types of meso-substituents can be prepared by a binary mixed aldehyde condensation [4,5]. However, this approach is statistical in nature and usually six porphyrins are formed [6]. Product isolation requires careful and tedious chromatographic separations, the yield is very poor and it is not always possible to isolate pure porphyrin. More direct approaches to trans-substituted porphyrins are provided by condensation of dipyrromethane with aldehyde [7]. This route requires access to meso-substituted dipyrromethane, which can be synthesized from the reaction of aldehyde with excess of pyrrole catalyzed by acid [7,8]. In this paper, 5-(4-X-phenyl)-10,15,20-tris(substituted phenyl) porphyrins (4-6) were synthesized from meso-(substituted phenyl) dipyrromethanes (1-3). The yields obtained using the dipyrromethane approach are considerably higher for porphyrins substituted by –OCH₃ (4) and -F (6) groups than when the binary mixed aldehyde and pyrrole condensation method was used. However, in spite of the fact that dipyrromethane 2 substituted by –N(CH₃)₂ was obtained with appreciable yield, it does not present any advantage, as far as yield is concerned, for the synthesis of porphyrin 5.

Results and Discussion

Dipyrromethane formation.

The condensation of substituted benzylaldehyde with a large excess of pyrrole (1:45 aldehyde/ pyrrole mol ratio) catalyzed by trifluoroacetic acid affords meso-(4-substituted phenyl) dipyrromethanes 1-3 (Scheme 1). Under these conditions, pyrrole serves both as the reactant in excess and as the solvent for the reaction. Complete consumption of the aldehyde was observed after stirring the mixture for 25 min at room temperature.

Scheme 1.

Scheme 1.

The dipyrromethanes 1, 2 and 3 were isolated by flash chromatography in 87, 75 and 92 % yields, respectively. A mildly basic medium (n-hexane/ethyl acetate/triethylamine ~1%) was used as eluant to prevent the decomposition of the dipyrromethane on the silica column used.

Dipyrromethanes 1-3 are stable in the purified form if stored at 0°C under nitrogen atmospheres and in the absence of light. The results show that this condensation reaction is compatible with aromatic aldehydes bearing -OCH₃, -N(CH₃)₂ and –F groups, widening the broad scope of these reactions [7,8].

Synthesis of porphyrins

Porphyrins 4-6 were synthesized by the acid-catalyzed condensation of dipyrromethanes 1-3 and the corresponding benzaldehyde derivatives in chloroform at room temperature (Scheme 2).

Scheme 2.

Scheme 2.

Mixed-benzaldehyde dipyrromethane condensations were performed using about [2.2:1.4:1] molar ratios of dipyrromethane, 4-X-benzaldehyde and substituted benzaldehyde. These amounts of reactants lead to better yields of the selected AB₃-porphyrins. Under the experimental conditions used the acid-catalyzed fragmentation of dipyrromethane leads to an increase in the formation of symmetric porphyrins. Consequently, this side reaction was minimized by adding a small excess of the 4-X benzaldehyde with respect to the substituted benzaldehyde. After this adjustment, the reaction mixture was subjected to oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The porphyrins were separated in high purity by flash chromatography using dichloromethane/methanol or acetone mixtures as eluants. In all these cases, the first purple band corresponds to the meso-tetra(substituted phenyl) porphyrin and the second is the desired AB₃-porphyrins (4-6), which were obtained in yields of 14, 0.3 and 12 %, respectively. In each case, the corresponding symmetrical porphyrins were formed in yields of 12, 0.5 and 10 %, respectively.

Another way of preparing these porphyrins, bearing two different types of meso-substituents, is a binary mixed aldehyde condensation. Thus, porphyrin 4 was synthesized using this procedure by heating a mixture of 4-acetamidobenzaldehyde, 3,5-methoxybenzaldehyde and pyrrole in propionic acid at 90 °C for 1 h. The reaction workup was not simple due to the difficulty of removing the propionic acid and the tars present. Porphyrin 4 was separated by slow column chromatography to yield 2.6 % of the desired compound. Porphyrin 5 was also prepared under similar conditions using a mixture of 4- acetamidobenzaldehyde, 4-N,N-dimethylaminobenzaldehyde and pyrrole yielding the desired product in a yield of ~0.4 % after a lenghty purification procedure [4]. The synthesis of porphyrin 6 via a modification of Lindsay’s method was previously reported in the literature [5]. The reaction of pentafluorbenzaldehyde, 4-carbomethoxybenzaldehyde and pyrrole was performed in chloroform using trifluoracetic acid as catalyst to yield ~1.5 % of porphyrin 6.

In conclusion, the reported results expand the scope of the AB₃-porphyrin synthesis using dipyrro- methane/benzaldehyde mixtures [8]. This method considerably increases the yields of porphyrins 4 and 6 in comparison with the binary mixed aldehyde condensation procedures. However, this pathway does not present any advantage in the synthesis of porphyrin 5, substituted by –N(CH₃)₂ groups. In this case, the presence of a high level of side products was detected. The amine group apparently produces an increase in the formation of open-chain oligomers, which complicate the porphyrin purification and the yield is considerably diminished. Trifluoroacetic acid, an alternative catalyst of these reactions instead of BF₃∙O(Et)₂, could diminish the acidolysis of 1,9-unsubstituted dipyrromethanes and the amount of oligomers formed [9]. Finally, the resulting amido porphyrins 4-6 can be hydrolyzed to the correponding amino porphyrins, which are interesting starting materials for preparing supramolecules linked by amide bond [1].