Unsymmetrically Substituted Porphyrins

A mild procedure which does not involve strong adds, has to be used in the synthesis of pure isomers of unsymmetrically substituted porphyrins from dipyrromethanes. The best procedure having been applied, e.g. in unequivocal syntheses of uroporphyrins II, III, and IV (see p. 251f.), is the condensation of 5,5 -diformyldipyrromethanes with 5,5 -unsubstituted dipyrromethanes in a very dilute solution of hydriodic add in acetic acid (A.H. Jackson, 1973). The electron-withdrawing formyl groups disfavor protonation of the pyrrole and therefore isomerization. The porphodimethene that is formed during short reaction times isomerizes only very slowly, since the pyrrole units are part of a dipyrromethene chromophore (see below). Furthermore, it can be oxidized immediately after its synthesis to give stable porphyrins. 

The 21//,22//-tautomer 2 with hydrogens at adjacent pyrrole rings is less stable because of penetration of each hydrogen into the van der Waals sphere of the other. However, NMR studies with unsymmetrically substituted porphyrins at low temperature have allowed the observation of both tautomers 1 and 2. The kinetic parameters of tautomerism investigated by NMR measurements at different temperatures are consistent with a two-step process forming 3 from 1 via 2 rather than a concerted two-hydrogen shift which could form 3 from 1 directly. 

A few current examples are shown below and include unsymmetrically substituted derivatives 14227, the cationic derivative 15228, the neutral derivative 16226 and the classic anionic derivative 17229 230, (tetrabenzoporphyrinato)zinc(II) , an intermediate structure between that of porphyrins and phthalocyanines, and have also been investigated in this respect. However, its quantum yield for singlet oxygen generation (0.023) in liposomes is much lower than that of Photofrin (0.19)177. 

The porphyrin part of haemoglobin is called haem, and it is an iron(II) complex. It is unsymmetrically substituted with carboxylic acid chains on one side and vinyl groups on the other. 

Cyclization of open-chain, suitably substituted tetrapyrroles affords the possibility of a linear synthesis of unsymmetrically substituted porphyrins. l-Bromo-19-methylbiladienes 23 are particularly... 

Perhaps the most important new development in the ac-biladiene route has been the synthesis of discrete unsymmetrical tripyrrene intermediates. Russian workers had shown that a,a -disubstituted pyrromethanes could be condensed successively with one and two formyl pyrrole units to form first a tripyrrene and then a symmetrical ac-biladiene, which could be cyclized to porphyrin. The Liverpool group, however, showed that by use of unsymmetrical differentially protected pyrromethane diesters, condensation could be effected with two different formyl pyrroles to yield first tripyrrenes and then unsymmetrical ac-bi-ladienes. Cyclization of the latter afforded unsymmetrically substituted porphyrins. This procedure represents the first truly stepwise rational porphyrin synthesis, as exemplified by the synthesis of isocoproporphyin (26) (cf. Scheme... 

While unsymmetrically substituted tetraaryl (and arylalkyl) porphyrins (for numbering see Fig. 1, Table 23) were prepared by reacting the corresponding aldehydes and separating the mixture via column chromatography [194] a solid phase synthesis was introduced for the preparation of tolylporphyrin [195], Polystyrene, crosslinked with 2% divinylbenzene, was reacted with 3-hydroxy-or 4-hydroxybenzaldehyde respectively and subsequently was treated with p-tolylaldehyde and pyrrole in hot propionic acid. Tetratolylporphyrin, also... 

Table 23. Unsymmetrically substituted tetraaryl (and arylalkyl) porphyrins (see Ref. 194)...

McMurry cross-coupling reactions have also been found to be useful for the synthesis of the unsymmetrically substituted bisporphyrin 68 and the porphyrin-chlorin heterodimer 69, which were isolated from mixtures of the corresponding homodimers [55] (Figure 6.14). 

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