Preliminary Free Energy Map of Prebiotic Compounds Formed from CO2, H2 and H2S.

What kinds of CHOS compounds might be formed in a prebiotic milieu by reducing CO2 in the presence of H2 and H2S? How might the presence of sulfur influence the chemical composition of the mixture? We explore these questions by using first-principles quantum chemistry to calculate the free energies of CHOS compounds in aqueous solution, by first generating a thermodynamic map of one- and two-carbon species. We find that while thiols are thermodynamically favored, thioesters, thioacids, and thiones are less favorable than their non-sulfur counterparts. We then focus on the key role played by mercaptoacetaldehyde in sulfur analogs of the autocatalytic formose reaction, whereby the thiol group introduces asymmetry and potential thermodynamic selectivity of some compounds over others.

Thermodynamics of Potential CHO Metabolites in a Reducing Environment.

How did metabolism arise and evolve? What chemical compounds might be suitable to support and sustain a proto-metabolism before the advent of more complex co-factors? We explore these questions by using first-principles quantum chemistry to calculate the free energies of CHO compounds in aqueous solution, allowing us to probe the thermodynamics of core extant cycles and their closely related chemical cousins. By framing our analysis in terms of the simplest feasible cycle and its permutations, we analyze potentially favorable thermodynamic cycles for CO2 fixation with H2 as a reductant. We find that paying attention to redox states illuminates which reactions are endergonic or exergonic. Our results highlight the role of acetate in proto-metabolic cycles, and its connection to other prebiotic molecules such as glyoxalate, glycolaldehyde, and glycolic acid.

Early Steps of Glycolonitrile Oligomerization: A Free-Energy Map.

Building on our previous free-energy map (J. Phys. Chem. A 2018, 122, 6769-6779) examining the reactions of monomeric glycolonitrile, we explore the formation of its dimers and trimers in aqueous solution under neutral conditions. While 5-membered rings are kinetically favored, open-chain oligomers with ester or amide linkages are thermodynamically favored. Accessing the 5-membered rings also provides a potential route to glyoxal that bypasses preforming glycolamide, the thermodynamic sink for monomers. However, finding a kinetically accessible route to glycine starting from glycolonitrile in the absence of added ammonia at room temperature proved challenging; the best case involved an intramolecular nucleophilic substitution reaction in a dimer containing neighboring imine and amide groups. Our free-energy map also examines routes to experimentally proposed moieties, explaining why some are observed in low yield or not at all.

Exploring Free Energy Profiles of Uracil and Cytosine Reactions with Formaldehyde.

Simple polymers can be potentially formed by the co-oligomerization of pyrimidine nucleobases, uracil and cytosine, with the small molecule formaldehyde. Using density functional calculations, we have constructed a free energy map outlining the thermodynamics and kinetics for (1) the addition of formaldehyde to uracil and cytosine to form hydroxymethylated uracil (HMU) and hydroxymethylated cytosine (HMC), (2) the deamination of cytosine and HMC to uracil and HMU, respectively, and (3) the initial oligomerization of 5-HMU. For the initial formation of monomeric HMU, addition of formaldehyde to the C5 and C6 positions is thermodynamically favored over N1 and N3, but faces higher kinetic barriers, and explains why 5-HMU is the main product observed experimentally. Oligomerization of 5-HMU is thermodynamically favorable although decreasingly so at the tetramer stage. In addition, decreasing concentrations of initial monomer shifts the equilibrium disfavoring oligomer formation.

Role of Acid in the Co-oligomerization of Formaldehyde and Pyrrole.

Building on previous work (J. Phys. Chem. A 2017, 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.

Reactions of Glycolonitrile with Ammonia and Water: A Free Energy Map.

Glycolonitrile, the product of combining CH2O and HCN, is an intermediate in the Strecker reaction leading to the synthesis of the amino acid glycine. However, besides glycine, a plethora of other compounds are also generated when CH2O and HCN react in the presence of ammonia and water. As a starting point to analyze the possible components of this complex mixture, we have employed density functional theory to construct a free energy map of all two-carbon (C2) species that may be present when glycolonitrile participates in addition or elimination reactions with ammonia and water. By identifying thermodynamic sinks and kinetic barriers, we find that the myriad C2 species can be grouped into three broad regions across the free energy landscape. This allows us to trace possible routes to glycine and other molecules of interest in the reaction mixture. The present map also extends our previous work on one-carbon (C1) species. We had previously found one issue with our computational protocol in the C1 map; however, our present C2 map provides a larger data set that supports using an empirical correction to our original protocol for imidic acid to amide transformations, without increasing the computational cost, while retaining the original protocol for other classes of reactions.

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 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.

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.

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 sp(2) six-membered ring is more stable compared to its monomers, the reverse is true for the nonplanar sp(3) six-membered rings formed by trimerization of formamidic acid or formamide.

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 (J. Phys. Chem. A 2013, 117, 12658).

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.

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.

Primordial ocean chemistry and its compatibility with the RNA world.

We examine the stability of three key components needed to establish an RNA World under a range of potential conditions present on the early earth. The stability of ribose, cytosine, and the phosphodiester bond are estimated at different pH values and temperatures by extrapolating available experimental data. The conditions we have chosen range from highly acidic or alkaline hydrothermal vents, to the milder conditions in a primordial ocean at a range of atmospheric CO(2) partial pressures.

Thermodynamics and kinetics of imidazole formation from glyoxal, methylamine, and formaldehyde: a computational study.

Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the mechanism of experimentally observed imidazole formation from the reaction of glyoxal and methylamine in solution. Our calculations suggest that a diimine species is an important intermediate in the reaction. Under acidic conditions, we find that the diimine acts as a nucleophile in attacking the carbonyl group of either formaldehyde or glyoxal to first generate an acyclic enol intermediate, which then goes on to close the ring and form imidazoles. Our results confirm that formaldehyde and, by extension, other small aldehydes are likely to be incorporated into imidazole ions in the presence of glyoxal and primary amines in clouds and aqueous aerosol. This is a new mechanism of aerosol formation by formaldehyde, the most abundant aldehyde in the atmosphere. The amount of aerosol formed will depend on the amounts of glyoxal and amines present.

Self-assembly of SbCl3 and 1,4-dioxane: cubic structure connected by very weak bonds.

The self-assembly of SbCl(3) and 1,4-dioxane in a 2:3 ratio leads to an interpenetrating extended cubic structure from X-ray crystallography. The structure is held together by very weak Sb-O bonds ( approximately 7 kcal/mol each), which still maintain strong directionality. Parameterization and subsequent simulation of the system using a reactive force field (ReaxFF) gives us insight into the key interactions necessary for self-assembly from a completely random configuration of molecules into the experimentally observed cubic structure. We explain why the porous structure (with no interpenetration of lattices) is not observed, and we trace the important intermediate substructures formed en route to the crystal.

Thermodynamics and kinetics of methylglyoxal dimer formation: a computational study.

Density functional theory (B3LYP//6-311+G*) calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the hydration of methylglyoxal and the subsequent formation of dimeric species in solution. Our calculations show that, unlike glyoxal, fully hydrated species are not thermodynamically favored over their less hydrated counterparts, nor are dioxolane ring species the thermodynamic sink, which is in agreement with experimental data. Instead, we find that aldol condensations are the most favored oligomerization reactions for methylglyoxal. These results differ from those of glyoxal, which, lacking the methyl group, cannot access the enol structure leading to aldol condensation. For methylglyoxal, the product from nucleophilic attack at the aldehyde rather than the ketone was favored. Our results help explain some of the observed differences between methylglyoxal and glyoxal, in particular the different array of oligomers formed.

Favoring heterotrimeric boroxine formation using an internal Lewis base: a computational study.

Heterotrimeric arylboroxines can be favorably formed by designing one of the arylboronic acid monomers to contain a pendant Lewis base. Using density functional theory (B3LYP//6-311+G*) calculations including Poisson-Boltzmann implicit solvent, we found that AB2 trimeric arylboroxines were thermodynamically favored over A2B, A3, or B3, where A and B are monomeric arylboronic acids with and without a pendant Lewis base, respectively. The most stable AB2 trimers were formed when the B monomer contained electron-withdrawing substituents, particularly halogens in the para-position or pi-acceptors in the meta-position. On the other hand, adding different para-substituents to the A monomer did not significantly change the energetics. Our calculations also suggest that ABC trimers with three different monomers will not be significantly favored over AB2 trimers when making small electronic perturbations, by changing the substituents on each monomer.

Hetero-arylboroxines: the first rational synthesis, X-ray crystallographic and computational analysis.

A novel series of hetero-arylboroxines were synthesized and structurally characterized by X-ray diffraction, NMR and computational analysis. The solid-state structures of the hetero-arylboroxines represent the first report of AB(2)-type hetero-arylboroxines.

Thermodynamics and kinetics of glyoxal dimer formation: a computational study.

Density functional theory (B3LYP//6-311+G) calculations including Poisson-Boltzmann implicit solvent were used to study the hydration of glyoxal and subsequent formation of dimeric species in solution. Our calculations show that the dioxolane ring dimer is the thermodynamic sink among all monomers and dimers with varying degrees of hydration. Although fully hydrated species are thermodynamically favored over their less hydrated counterparts, we find that a preliminary dehydration step precedes dimerization and ring closure. Ring closure of the open dimer monohydrate to the dioxolane ring dimer is kinetically favored over both hydration to the open dimer dihydrate and ring closure to form the dioxane ring dimer. The kinetic barriers for different geometric approaches for dimerization suggest an explanation why oligomerization stops after the formation of a dioxolane ring trimer as observed experimentally.

Thermodynamics and kinetics of methylboroxine.amine adduct formation: a computational study.

Density functional theory (B3LYP//6-311+G*) calculations including Poisson-Boltzmann implicit solvent were applied to study the formation of the trimethylboroxine.amine adduct with respect to methylboronic acid monomers and free amine in solution. Potential intermediates and transition states between intermediates were calculated to assess the thermodynamic and kinetic factors controlling this transformation. Our calculations suggest that the rate-determining steps are condensation reactions to form dimers and trimers, and closure of the boroxine ring. Fast amine exchange is expected throughout the transformation, and the most-stable intermediate is a dimer.amine adduct. Using our calculated barriers for the methyl system as a template, we assess the conversion of phenylboronic acid to the triphenylboroxine.amine adduct and find that the pathway is most likely similar, except that the transformation is thermodynamically and kinetically more favored for the phenyl system in the presence of pyridine.