Considerable progress has been made in recent years in the search for synthetic methods leading to functionalized porphyrins, especially for modification of either the β‐ or meso positions. For the latter, total synthesis based on condensation methods or partial synthesis through functionalization of preformed porphyrin have emerged as possible methods. The increasing number of possible technical and medicinal applications for unsymmetrically meso‐substituted porphyrins requires straightforward methods for the preparation of the so‐called ABCD‐porphyrins, i.e., porphyrins with up to four different meso substituents. Here, we describe new strategies for the synthesis of ABCD‐type porphyrins based on porphyrin reactions with organolithium reagents and the use of Pd‐catalyzed coupling reactions. With the whole repertoire of contemporary functionalization methods, a comprehensive analysis and comparison of the various strategies for A‐, AB‐, A2B‐, ABC‐, A2BC‐ and ABCD‐type porphyrins is given. In addition, we report on the synthesis of new functionalized derivatives for some of these porphyrin classes. In practical terms and taking an applied‐science‐oriented approach, the synthesis of unsymmetrically meso‐substituted porphyrins is best accomplished by a combination of well‐developed condensation methods with subsequent functionalization by organolithium compounds or transition‐metal‐catalyzed coupling protocols. The methods described are suitable for the preparation of porphyrins for many divergent applications ranging over amphiphilic porphyrins for photodynamic therapy, push‐pull systems for optical applications and chiral systems useful in catalysis to donor–acceptor systems suitable for electron‐transfer studies.

General syntheses have been developed for meso-substituted porphyrins with one or two substituents in the 5,10-positions and no beta substituents. 5-Substituted porphyrins with only one meso substituent are easily prepared by an acid-catalyzed condensation of dipyrromethane, pyrrole-2-carbaldehyde, and an appropriate aldehyde using a "[2+1+1]" approach. Similarly, 5,10-disubstituted porphyrins are accessible by simple condensation of unsubstituted tripyrrane with pyrrole and various aldehydes using a "[3+1]" approach. The yields for these reactions are low to moderate and additional formation of either di- or monosubstituted porphyrins due to scrambling of the intermediates is observed. However, the reactions can be performed quite easily and the desired target compounds are easily removed due to large differences in solubility. A complementary and more selective synthesis involves the use of organolithium reagents for S(N)Ar reactions. Reaction of in situ generated porphyrin (porphine) with 1.1-8 equivalents of RLi gave the monosubstituted porphyrins, while reaction with 3-6 equivalents of RLi gave the 5,10-disubstituted porphyrins in yields ranging from 43 to 90 %. These hitherto almost inaccessible compounds complete the series of different homologues of A-, 5,15-A(2)-, 5,10-A(2)-, A(3)-, and A(4)-type porphyrins and allow an investigation of the gradual influence of type, number, and regiochemical arrangement of substituents on the properties of meso-substituted porphyrins. They also present important starting materials for the synthesis of ABCD porphyrins and are potential synthons for supramolecular materials requiring specific substituent orientations.

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Vilsmeier formylation is one of the most widely used substitution reactions for the functionalization of porphyrins. However, its utility is limited by the electrophilic/acidic reaction conditions, deactivation of the aromatic system and regiochemical problems, the requirement for metal complexes and necessity for subsequent demetalation under harsh conditions, and low functional group tolerance. To overcome these limitations, the dithianyl group has been utilized as a latent formyl synthon in porphyrin chemistry. 2-Formyl-1,3-dithiane can be used directly in pyrrole condensation reactions to regioselectively yield porphyrins with up to four dithianyl residues. Likewise, 5-dithianyldipyrromethane could be prepared quantitatively as a key building block for various porphyrin condensation reactions yielding the respective free base formylporphyrins after deprotection. Additionally, dithianyllithium can be used as a reagent for the direct aromatic substitution of metallo- and free base porphyrins under nucleophilic conditions.