Synthetic Routes to meso-Patterned Porphyrins

Abstract

Synthetic meso-substituted porphyrins offer significant attractions compared with naturally occurring beta-substituted porphyrins. The attractions include the rectilinear arrangement of the four meso substituents and potential synthetic amenability from pyrrole and simple acyl reactants, thereby avoiding the cumbersome syntheses of beta-substituted pyrroles. In practice, however, the classical methods for the synthesis of meso-substituted porphyrins were characterized by high-temperature reactions, limited scope of substituents, and statistical mixtures accompanied by laborious chromatography if porphyrins bearing two different types of substituents were sought. Such methods left unrealized the tremendous utility of meso-substituted porphyrins across the enormously broad field of porphyrin science, which touches pure chemistry; energy, life and materials sciences; and medicine. This Account surveys a set of strategies, developed over a generation, that provide rational access to porphyrins bearing up to four distinct meso substituents. A "2 + 2" route employs a dipyrromethane-1,9-dicarbinol and a dipyrromethane (bearing ABC- and D-substituents, respectively) in a two-step, one-flask process of acid-catalyzed condensation followed by oxidation at room temperature to form the free base "ABCD-porphyrin." A "bilane" route relies on the acid-catalyzed reaction of a 1-acyldipyrromethane (CD substituents) and a 9-bromodipyrromethane-1-carbinol (AB substituents) to form the corresponding 19-acyl-1-bromobilane. Reaction of the latter compound in the presence of MgBr(2), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and toluene at reflux exposed to air affords the corresponding magnesium(II) porphyrin. The two routes are complementary, both in scope and in implementation. A suite of methods also affords trans-A(2)B(2)-porphyrins by reaction of a dipyrromethane and an aldehyde, self-condensation of a dipyrromethane-1-carbinol, or self-condensation of a 1-acyldipyrromethane. These new routes are also useful for preparing sparsely substituted porphyrins, which bear fewer than four meso substituents (e.g., trans-AB-porphyrins, A-porphyrins). Because of their compact size and the ability to incorporate hydrophilic or amphipathic groups, such molecules are ideal for biological applications. The success of these new synthetic strategies has relied on a number of advances including (1) the development of simple yet efficient routes to dipyrromethanes, acyldipyrromethanes, and dipyrromethane-carbinols, (2) the identification of acid catalysts and reaction conditions for condensations of pyrromethane species without accompanying acidolysis (which underlies scrambling and formation of a mixture of porphyrin products), (3) the development of analytical methods to rapidly screen for scrambling and to characterize the distribution of oligopyrromethanes and macrocycles, (4) selection and refinement of synthetic methods to increase yields and to limit or avoid use of chromatography, thereby achieving scalability to multigram levels, and (5) exploitation of discoveries concerning the fundamental chemistry of pyrrolic species. With these developments, the prior era of porphyrin synthesis has been supplanted with rational routes that proceed under very mild conditions and afford a single porphyrin bearing up to four distinct meso substituents. The meso substituents encompass a very wide range of molecular complexity. The resulting porphyrins can serve as building blocks in the construction of model systems, as components of molecular materials, and as surrogates for naturally occurring tetrapyrrole macrocycles.