In 1960, MacDonald and coworkers introduced a new method for porphyrin synthesis that involved the acid-catalyzed condensation of dipyrrylmethane dialdehydes with [Formula: see text],[Formula: see text]-diunsubstituted dipyrrylmethanes or the related dicarboxylic acids, followed by an air oxidation. The key bond forming steps entail electrophilic substitution at two pyrrole units with the aldehyde moieties to generate, following elimination of water, a 5,15-dihydroporphyrin or porphodimethene intermediate. Following addition of sodium acetate, or in later procedures zinc acetate, the dihydroporphyrins readily air oxidize to the fully aromatic porphyrin system. This strategy, which parallels chemistry contemporaneously developed by R. B. Woodward at Harvard for the total synthesis of chlorophyll [Formula: see text], demonstrated that dipyrrylmethanes were sufficiently stable to be utilized as intermediates in porphyrin syntheses and that porphodimethene formation circumvented acidolytic scrambling reactions that might lead to isomeric porphyrin products. This type of chemistry was later adapted by Johnson, Woodward and others to prepare porphyrin-type systems by a “3 + 1” strategy, or expanded porphyrins by “3 + 2” or other combinations of oligopyrrolic precursors. In recent years, the term “MacDonald condensation” has been increasingly used to describe other types of chemistry involving oligopyrrolic intermediates. Following on from a historical review of this area, guidelines for the identification of MacDonald-type reactions are proposed.
Classic highlights in porphyrin and porphyrinoid total synthesis and biosynthesis
