Pyrrole (Acros Organics, distilled from CaH₂), benzaldehyde (Aldrich, distilled), indium (III) chloride 98% (Aldrich), NaOH (20-40 mesh beads)

Pyrrole (5.20 L, 75.0 mol) and benzaldehyde (79.8 g, 0.752 mol) were added to a 12-L two-neck round-bottomed flask equipped with a mechanical stirrer. The solution was degassed with a stream of argon for 1 h. InCl₃ (16.7 g, 75.5 mmol) was added, and the mixture was stirred under argon at room temperature for 1.5 h. The mixture was yellow during the course of the reaction. The reaction was quenched by the addition of NaOH (90.1 g, 2.25 mol). The mixture was stirred for 1.5 h. The stirrer was stopped, and the mixture was allowed to settle for 1 h. The mixture was filtered (Fisher brand qualitative filter paper) using a Büchner funnel. The flask and filtered material on the funnel was washed with pyrrole (350 mL). The filtered material after drying under vacuum with warming for 4 h constituted 118 g. The filtrate was concentrated using a rotary evaporator under vacuum (0.2 mmHg) at 40-60 °C (the trap was cooled in a dry ice-acetone bath). The amount of recovered pyrrole was 5.30 L. A crude viscous residue was left in the evaporation flask. The crude viscous residue was treated with hexanes to remove traces of pyrrole in the following manner four times: hexanes (450 mL) was added, and the volatile components were removed under vacuum. The crude product was obtained as a pale yellow solid. Recrystallization [ethanol/water (4:1), 1 L] afforded 115.5 g of 5-phenyldipyrromethane (69% yield). The recovered liquid (5.30 L), which contains predominantly pyrrole and residual water, was distilled. The recovered pyrrole (4.92 L, 90% recovery based on unreacted pyrrole) was suitable for reuse. Note: The progress of the reaction was monitored by TLC and GC analysis of the unreacted benzaldehyde. It is imperative to obtain the crude mixture as a solid prior to initializing crystallization. The presence of a trace amount of pyrrole or unreacted benzaldehyde in the crude mixture complicates the crystallization process. A combination of ethanol and water is extremely useful solvent for crystallization of the crude mixture. The crude solid was dissolved in a minimum amount of boiling ethanol followed by dropwise addition of water until a trace of turbidity appeared. A few more drops of boiling ethanol was added to that to obtain a clear solution. A recommended solvent for chromatographic purification of meso-substituted dipyrromethanes is hexanes/CH₂Cl₂/ethyl acetate (7:2:1) although hexanes/ethyl acetate mixture (4:1) is a good solvent for TLC analysis (R_f = 0.53).

The one-flask solventless reaction of an aldehyde (aromatic or aliphatic) with excess pyrrole (100:1 ratio of pyrrole to aldehyde) in the presence of InCl₃ as catalyst provides a simple means of preparing the corresponding meso-substituted dipyrromethane. The large excess of pyrrole is required in this reaction to avoid the formation of byproducts in significant amount. Catalysis can be achieved with other Lewis acid such as MgBr₂, Yb(OTf)₃, or Sc(OTf)₃. The use of InCl₃ largely eliminates the formation of byproducts in significant amount, thereby facilitating crystallization. The concentration of catalyst depends upon the aldehyde substrate. Following removal and recovery of excess pyrrole, the dipyrromethane is obtained by crystallization. The simplicity of this procedure (no aqueous/organic extraction, distillation, or chromatography) minimizes waste and enables scalability. The N-confused dipyrromethane and the tripyrrane species are dominant byproducts of the reaction. Because the former is an isomer while the latter is an oligomer of the dipyrromethane, a satisfactory elemental analysis is a necessary but insufficient criterion of purity. Therefore, purity of dipyrromethanes is best judged by GC or HPLC analysis.

¹H NMR (CDCl₃) 5.47 (s, 1H), 5.91 (m, 2H), 6.15 (m, 2H), 6.69 (m, 2H), 7.35-7.19 (m, 5H), 7.89 (bs, 2H)

Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S. Org. Process Res. Dev. 2003, 7, 799–812

Lee, C. -H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427