Investigation of Conditions Giving Minimal Scrambling in the Synthesis of trans-Porphyrins from Dipyrromethanes and Aldehydes

• Published in: Journal of organic chemistry 1999-04, Vol.64 (8), p.2864-2872
• Main Authors: Littler, Benjamin J, Ciringh, Yangzhen, Lindsey, Jonathan S
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo982452o

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 CH2Cl2 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 °C with BF3·Et2O catalysis in the presence of NH4Cl followed by DDQ oxidation and (2) condensation at 0.1 M in DMSO at 100 °C in the presence of NH4Cl (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.