No abstract

Porphyrins bearing specific patterns of substituents are crucial building blocks in biomimetic and materials chemistry. We have developed methodology that avoids statistical reactions, employs minimal chromatography, and affords up to gram quantities of regioisomerically pure porphyrins bearing predesignated patterns of up to four different meso substituents. The methodology is based upon the availability of multigram quantities of dipyrromethanes. A procedure for the diacylation of dipyrromethanes using EtMgBr and an acid chloride has been refined. A new procedure for the preparation of unsymmetrical diacyl dipyrromethanes has been developed that involves (1) monoacylation with EtMgBr and a pyridyl benzothioate followed by (2) introduction of the second acyl unit upon reaction with EtMgBr and an acid chloride. The scope of these acylation methods has been examined by preparing multigram quantities of diacyl dipyrromethanes bearing a variety of substituents. Reduction of the diacyl dipyrromethane to the corresponding dipyrromethane-dicarbinol is achieved with NaBH(4) in methanolic THF. Porphyrin formation involves the acid-catalyzed condensation of a dipyrromethane-dicarbinol and a dipyrromethane followed by oxidation with DDQ. Optimal conditions for the condensation were identified after examining various reaction parameters (solvent, temperature, acid, concentration, time). The conditions identified (2.5 mM reactants in acetonitrile containing 30 mM TFA at room temperature for <7 min) provided reaction without detectable scrambling (LD-MS) for aryl-substituted dipyrromethanes, and trace scrambling for alkyl-substituted dipyrromethanes. The desired porphyrins were obtained in 14-40% yield. The synthesis is compatible with diverse functionalities: amide, aldehyde, carboxylic acid, ester, nitrile, ether, bromo, iodo, ethyne, TMS-ethyne, TIPS-ethyne, perfluoroarene. In total 30 porphyrins of the types A(3)B, trans-A(2)B(2), trans-AB(2)C, cis-A(2)B(2), cis-A(2)BC, and ABCD were prepared, including >1-g quantities of three porphyrins.

A diverse range of reaction conditions for the MacDonald-type 2 + 2 condensation of a 5-substituted dipyrromethane and an aldehyde has been studied with the goal of eliminating acid-catalyzed polypyrrolic rearrangement reactions in the synthesis of trans-porphyrins. A rapid screening method based on laser desorption mass spectrometry has enabled the degree of rearrangement to be examined as a function of the acid catalyst, reagent concentration, reagent stoichiometry, solvent, salts, and temperature. For condensations involving 5-mesityldipyrromethane, we identified reaction at 10 mM concentration in CH(2)Cl(2) with 17.8 mM TFA as optimal conditions for suppression of the rearrangement reaction. A synthetic procedure based on these conditions allowed the expedient synthesis of multigram batches of eight trans-porphyrins in 48-14% yield from 5-mesityldipyrromethane, with minimal chromatography. The same conditions were also effective for the synthesis of two trans-porphyrins derived from 5-(2,6-dichlorophenyl)dipyrromethane. Application of the same conditions to condensations involving 5-phenyldipyrromethane showed extensive rearrangement. Examination of a wide range of conditions showed that slow reactions are associated with less rearrangement. Two sets of conditions were identified that gave little or no scrambling: (1) condensation at 10 mM in MeCN at 0 degrees C with BF(3).Et(2)O catalysis in the presence of NH(4)Cl followed by DDQ oxidation and (2) condensation at 0.1 M in DMSO at 100 degrees C in the presence of NH(4)Cl (with no added acid catalyst) with air oxidation. Although yields are typically less than 10%, the elimination of the need to perform tedious chromatography improves the methodology available for the preparation of trans-porphyrins, derived from sterically unhindered dipyrromethanes.

The condensation of an aldehyde with a dipyrromethane bearing a sterically unhindered aryl substituent at the 5-position typically results in low yield and a mixture of porphyrin products derived from acidolytic scrambling. We have developed a concise nonscrambling synthesis of such trans-porphyrins that takes advantage of the availability of multigram quantities of dipyrromethanes. This route involves the selective monoacylation of the dipyrromethanes with a pyridyl thioester, reduction of the monoacyl dipyrromethane to the corresponding carbinol, and self-condensation of the carbinol to form the porphyrin. The monoacylation procedure has wide scope as demonstrated by the preparation of a set of 15 diverse monoacyl dipyrromethanes in good yield at the multigram scale. The dipyrromethanecarbinol self-condensation reaction is extremely rapid (<3 min) under mild room-temperature conditions and affords the trans-porphyrin in 16-28% yield. Analysis by laser-desorption mass spectrometry (LD-MS) of samples from the crude reaction mixture revealed no scrambling within the limit of detection (1 part in 100). The self-condensation is compatible with a range of electron-withdrawing or -releasing substituents as well as substituents for building block applications (TMS-ethyne, ethyne, iodo, ester). The absence of any detectable scrambling in the self-condensation enables a simple purification. The synthesis readily affords gram quantities of pure, sterically unhindered trans-porphyrins in a process involving minimal chromatography.

The use of heteroatom-substituted porphyrins in bioorganic and materials chemistry requires the ability to position a variety of substituents in a controlled manner about the porphyrin periphery. We describe a rational route to trans-AB 2 C-type porphyrins bearing one oxygen atom (N 3 O) or one sulfur atom (N 3 S) in a designated location in the porphyrin core. The synthesis involved four stages: (1) Acid-catalyzed condensation of a furyl-or thienylcarbinol in excess pyrrole afforded the aryl-substituted furyl-or thienylpyrromethane in high yield. (2) Treatment of the furyl-or thienylpyrromethane with an acid chloride catalyzed by SnCl 4 or AlCl 3 afforded the corresponding diketo product. (3) Reduction with NaBH 4 in alcoholic solvents gave the furyl-or thienylpyrromethanediols. (4) Reaction of a furylpyrromethanediol, thienylpyrromethanediol, or dipyrromethanediol with a dipyrromethane in a one-flask process of condensation followed by oxidation gave the corresponding porphyrin. Reaction conditions previously identified to minimize scrambling in a dipyrromethane-aldehyde condensation were found to be effective in this application. Thus, reaction with 10 mM reactants in acetonitrile at 0 °C containing BF 3 ‚Et 2 O and NH 4 Cl followed by oxidation with DDQ resulted in the desired porphyrin (10-20% yields) without acidolysis. In this manner, N 3 O-, N 3 S-, or N 4 -porphyrins bearing 5-(p-iodophenyl), 15-[4-(2-(trimethylsilyl)ethynyl)phenyl], and 10,20-di-p-tolyl groups have been made. This set of trans-substituted porphyrin building blocks is expected to be useful in the synthesis of biomimetic energy transduction systems.