We have investigated the nonoxidative stepwise co-oligomerization of formaldehyde and pyrrole to form porphinogen using density functional theory calculations that include free energy corrections. While the addition of formaldehyde to the pyrrole nitrogen is kinetically favored, thermodynamics suggest that this reaction is reversible in aqueous solution. The more thermodynamically favorable addition of formaldehyde to the ortho-carbon of pyrrole begins a stepwise process, forming dipyrromethane via an azafulvene intermediate. Subsequent additions of formaldehyde and pyrrole lead to bilanes (linear tetrapyrroles), which favorably cyclize to form porphinogen. Porphinogen is a precursor to porphin, the simplest unsubstituted porphyrin that could have played a role in primitive metabolism at the origin of life.

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Building on previous work (J. Phys. Chem. A2017,121, 8154–8166) under neutral conditions, we examined the co-oligomerization of CH2O and pyrrole to form porphryinogen under acidic conditions using density functional theory (B3LYP//6-311G**). Thermodynamically, we found that azafulvene intermediates were significantly stabilized under highly acidic conditions. Kinetically, energy barriers were lowered for C–C bond formation, discriminating in favor of reactions that lead to porphyrinogen. However, it was challenging to satisfactorily combine our thermodynamic and kinetic profiles into a unified free-energy profile because of difficulties in optimizing transition states of cationic species involving proton hops. Instead, we used neutral carboxylic acids as a proxy to study how energy barriers changed. By combining data from both neutral and acidic conditions, we estimate a free-energy profile for the initial steps of oligomerization under milder acidic conditions more relevant to prebiotic chemistry.