Porphinogen Formation from the Co-Oligomerization of Formaldehyde and Pyrrole: Free Energy Pathways

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 <i>ortho</i>-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

HCN, Formamidic Acid, and Formamide in Aqueous Solution: A Free-Energy Map

What chemical species might be found if water or ammonia reacts with HCN in aqueous solution under neutral conditions? Is it energetically favorable for formamidic acid, the first hydration product of HCN, to tautomerize into formamide under standard conditions? Do these molecules form stable oligomers in solution? To answer these questions, we constructed a Gibbs free-energy map of the molecules that might be present to evaluate their relative thermodynamic and kinetic stability. Our protocol utilizes density functional theory calculations, Poisson–Boltzmann implicit solvent, and thermodynamic corrections. We find that for C₁ species, formamide is indeed the thermodynamic sink, although the initial barrier to hydration is ∼30 kcal/mol. Molecules with one carbon and three heteroatoms are less stable. We also find that for HCN trimerization, although the planar sp² six-membered ring is more stable compared to its monomers, the reverse is true for the nonplanar sp³ six-membered rings formed by trimerization of formamidic acid or formamide

Preliminary Oligomerization in a Glycolic Acid–Glycine Mixture: A Free Energy Map

Glycolic acid and glycine can potentially self-oligomerize or co-oligomerize in solution by forming ester and amide bonds. Using density functional theory with implicit solvent, we have mapped a baseline free energy landscape to compare the relative stabilities of monomers, dimers, and trimers in solution. We find that amide bond formation is favored over ester bond formation both kinetically and thermodynamically, although the differences decrease when zwitterionic species are taken into account. The replacement of ester linkages by amide bonds is favored over lengthening the oligomer, suggesting that one route to oligopeptide formation is utilizing oligoesters as a starting point. We also find that diketopiperazine, the cyclic dimer of glycine, is favored over the linear dimer; however, the linear trimers are favored over their cyclic counterparts. Because glycolic acid and glycine are dominant products from a Strecker synthesis starting from formaldehyde and HCN, this study sheds light on potential pathways to prebiotic formation of oligopeptides via oligoesters

Mapping the Kinetic and Thermodynamic Landscape of Formaldehyde Oligomerization under Neutral Conditions

Density functional theory calculations, including Poisson–Boltzmann implicit solvent and free energy corrections, are applied to study the thermodynamic and kinetic free energy landscape of formaldehyde oligomerization up to the C₄ species in aqueous solution at pH 7. Oligomerization via C–O bond formation leads to linear polyoxymethylene (POM) species, which are the most kinetically accessible oligomers and are marginally thermodynamically favored over their oxane ring counterparts. On the other hand, C–C bond formation via aldol reactions leads to sugars that are thermodynamically much more stable in free energy than POM species; however, the barrier to dimerization is very high. Once this initial barrier is traversed, subsequent addition of monomers to generate trimers and tetramers is kinetically more feasible. In the aldol reaction, enolization of the oligomers provides the lowest energy pathway to larger oligomers. Our study provides a baseline free energy map for further study of oligomerization reactions under catalytic conditions, and we discuss how this will lead to a better understanding of complex reaction mixtures with multiple intermediates and products

Free Energy Map for the Co-Oligomerization of Formaldehyde and Ammonia

Density functional theory calculations, including Poisson–Boltzmann implicit solvent and free energy corrections, are applied to construct a free energy map of formaldehyde and ammonia co-oligomerization in aqueous solution at pH 7. The stepwise route to forming hexamethylenetetramine (HMTA), the one clearly identified major product in a complex mixture, involves a series of addition reactions of formaldehyde and ammonia coupled with dehydration and cyclization reactions at key steps in the pathway. The free energy map also allows us to propose the possible identity of some major peaks observed by mass spectroscopy in the reaction mixture being the result of stable species not along the pathway to HMTA, in particular those formed by intramolecular condensation of hydroxyl groups to form six-membered rings with ether linkages. Our study complements a baseline free energy map previously worked out for the self-oligomerization of formaldehyde in solution at pH 7 using the same computational protocol and published in this journal (<i>J. Phys. Chem. A</i> <b>2013</b>, <i>117</i>, 12658)

Glycolaldehyde Monomer and Oligomer Equilibria in Aqueous Solution: Comparing Computational Chemistry and NMR Data

A computational protocol utilizing density functional theory calculations, including Poisson–Boltzmann implicit solvent and free energy corrections, is applied to study the thermodynamic and kinetic energy landscape of glycolaldehyde in solution. Comparison is made to NMR measurements of dissolved glycolaldehyde, where the initial dimeric ring structure interconverts among several species before reaching equilibrium where the hydrated monomer is dominant. There is good agreement between computation and experiment for the concentrations of all species in solution at equilibrium, that is, the calculated relative free energies represent the system well. There is also relatively good agreement between the calculated activation barriers and the estimated rate constants for the hydration reaction. The computational approach also predicted that two of the trimers would have a small but appreciable equilibrium concentration (>0.005 M), and this was confirmed by NMR measurements. Our results suggest that while our computational protocol is reasonable and may be applied to quickly map the energy landscape of more complex reactions, knowledge of the caveats and potential errors in this approach need to be taken into account