Rational Syntheses of Porphyrins Bearing up to Four Different Meso Substituents

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.

Boron-Complexation Strategy for Use with 1-Acyldipyrromethanes

“…After 30 min, the mixture was passed through a pad of silica (4 x 8 cm) eluting with CH 2 Cl 2 . The product eluted as a fastmoving yellow band, which upon concentration afforded an orange oil (0.344 g, 91%): 1 Borabicyclo[3.3.1]non-9-yl)-1-(4-methylbenzoyl)-5-phenyldipyrromethane (6a-BBN) A solution of 2a (0.680 g, 2.00 mmol) in CH 2 Cl 2 (4 mL) was treated with TEA (0.670 mL, 4.80 mmol) followed by 9-BBN-OTf (8.00 mL, 4.00 mmol, 0.5 M in hexanes). After 30 min, the mixture was passed through a pad of silica (4 x …”

“…Following the procedure for 6a-BBN, reaction of 2b (0.529 g, 2.00 mmol) afforded a yelloworange solid (0.696 g, 91%): mp 147 °C (dec.); 1 …”

“…The synthesis of a 1-acyldipyrromethane (2) is achieved by treatment of a dipyrromethane (1) with EtMgBr in THF at room temperature followed by addition of a pyridyl thioester (5) in THF at -78 °C. 2 The product mixture consists of unreacted dipyrromethane (1), the 1-acyldipyrromethane (2), and pyridyl thioester and/or other byproducts (Scheme 1).…”

Palladium-Catalyzed Polyfluorophenylation of Porphyrins with Bis(polyfluorophenyl)zinc Reagents

“…The construction of porphyrins and related tetrapyrrolic macrocycles has attracted much interest [1][2][3][4][5][6] because they have a variety of important applications in many fields [7,8], including catalysis [9][10][11][12][13][14], medicine [15][16][17][18], and materials [19][20][21][22][23][24][25][26][27]. It is also well documented that the chemical, physical, and biological properties of porphyrin macrocycles can be systematically tuned by the electronic, steric and conformational environments of their peripheral substituents [7,8].…”

“…Penta-fluoro-phenyl and related polyfluorophenyl groups are one of the most important peripheral substituents in that their strong electron-withdrawing nature can greatly affect the electronic properties of a porphyrin core [25,27]. Conventional approaches to synthesizing pentafluorophenyl-substituted porphyrins involve multiple condensation reactions of pentafluorobenzaldehydes by using various monopyrroles or substituted dipyrromethanes under acidic conditions, followed by oxidation of the OPEN ACCESS resulting porphyrinogen intermediates [26][27][28][29][30]. However, these multiple-condensation methods have low yields, significant side products, and difficult purifications.…”