Selective Double Functionalization of meso‐Tetraphenylporphyrin Complexes on the Same Pyrrole Unit by Tandem Electrophilic/Nucleophilic Aromatic Substitution

Abstract

The mono-nitrated meso-tetraphenylporphyrin (TPP) complex 2 could be readily functionalized on the substituted pyrrole ring with yields of up to 83%. These transformations were achieved via aromatic substitution with carbanions generated from diverse functionalized compounds containing different leaving groups (3a ± g, Scheme 1). The resulting TPP compounds 4a ± g, bearing two different b-substituents on the same pyrrole ring, may be further manipulated. This, in turn, should allow one to tune the solubility of TPP derivatives used in photodynamic cancer therapy.Introduction. ± Porphyrins are important compounds intensively studied in recent years [1]. From a synthetic point of view, the selective functionalization of readily available meso-tetraphenylporphyrin (TPP) and its derivatives is of significant importance due to their potential use as sensitizers in photodynamic cancer therapy [2]. We have recently published two papers describing a convenient method for the selective mono-nitration in b-position of Zn, Cu, Ni, and Co TPP complexes by means of 25 ± 50% aqueous HNO 3 in CHCl 3 [3].A NO 2 group in the ring makes porphyrins, as well as aromatic systems in general, susceptible to nucleophilic attack. Of particular importance is the nucleophilic aromatic substitution of a H-atom by a carbanion made from precursors of type XÀCH 2 ÀY, where X and Y are leaving and stabilizing groups, respectively. Mechanistically, this kind of transformation proceeds according to the vicarious nucleophilic substitution (VNS) scheme [4]. Recently, several papers concerning this type of substitution in meso-aryl rings have been published [5].

Attempts of the Synthesis of Highly Functionalized Porphyrins at the β-Positions: Nitration of Exhaustively Substituted Moieties in the ’Eastern Half ’ and Mass-Spectral Study of the Reaction Products

“…This type of intermediates could undergo oxidation to give final products (M=1202 or 1247). Thus, the three compounds we observed should have structures as above (7)(8)(9). The reaction is similar to the fused heterocycles formation pathway (especially indole derivatives).…”

“…It was previously obtained from the corresponding dinitro-porphyrin derivative by vicarious nucleophilic substitution methodology (Scheme 1). [8,10] Thus, the introduction of the next NO 2 group(s) ought to result in the functionalization of one or two the remaining pyrrole units. These groups should allow again the vicarious nucleophilic substitution of hydrogen reaction leading to the hexaor even octasubstituted porphyrins at the β-positions.…”

“…Numerous reactions and various methods of activation of the system are utilized. [3][4][5][6][7][8][9] Previously the preparation of poly-substituted derivatives in meso-aryl rings was demonstrated. [3,4,7] Herein, attempts of synthesizing β-multifunctionalized porphyrins are reported.…”

Corrole and nucleophilic aromatic substitution are not incompatible: a novel route to 2,3-difunctionalized copper corrolates

“…The products were obtained in lower yields if compared with similar nucleophilic aromatic substitution of hydrogen reactions reported for nitroporphyrins. 33 We can account for this by pointing out that the choice of toluene/ethanol mixture as reaction medium was undoubtedly unfavourable for the nucleophilic attack, but it was compelled to the need of mantaining the copper nitrocorrolate in the neutral form. Moreover, the not entirely negligible decomposition observed in all the tested reactions was due to the dramatic sensitivity in basic environments usually displayed by copper corrolates.…”

Regiospecific naphthyl nitration of 5,10,15,20‐tetranaphthylporphyrin

“…For this reason and because of our interest in developing new porphyrin‐based sensitizers for our radioimmunotherapy program, TNP was chosen to be nitrated as its enlarged conjugated rings offer more sites for substitution than the corresponding phenyl compounds and, therefore, might serve as a precursor to various compounds of potential medical application in high yield 9. Moreover, although there have been some reports on the nitration of TPP and a lot of asymmetric porphyrins from nitro‐TPP have been synthesized,10–18 to the best of our knowledge, no work of selective nitration of TNP has been reported so far.…”