Formose Reaction Research Articles

Exploring the Core Formose Cycle: Catalysis and Competition.

The core autocatalytic cycle of the formose reaction may be enhanced or eroded by the presence of simple molecules at life's origin. Utilizing quantum chemistry, we calculate the thermodynamics and kinetics of reactions both within the core cycle and those that deplete the reactants and intermediates, such as the Cannizzaro reaction. We find that via disproportionation of aldehydes into carboxylic acids and alcohols, the Cannizzaro reaction furnishes simple catalysts for a variety of reactions. We also find that ammonia can catalyze both in-cycle and Cannizzaro reactions while hydrogen sulfide does not; both, however, play a role in sequestering reactants and intermediates in the web of potential reactions.

Developing a Design Guideline of Boronic Acid Derivatives to Scavenge Targeted Sugars in the Formose Reaction Products using DFT-based Machine Learning

Abstract Formose reaction facilitates the synthesis of sugars from HCHO, yet the valuable sugars constitute only a small portion of the total products. This necessitates the need for a chemical scavenger capable of selectively capturing only valuable sugars. With over 600,000 potential combinations of boronic acid-based scavengers available, pursuing a deductive search approach is unfeasible. This study aims to derive guidelines for designing scavengers that readily bind with target sugars while avoiding non-target ones, via machine learning informed by DFT calculations.

Saccharide formation by sustainable formose reaction using heterogeneous zeolite catalysts.

The formose reaction is a unique chemical reaction for the preparation of saccharides from formaldehyde, a single carbon compound. We applied zeolite materials as heterogeneous catalysts to the formose reaction. The simple addition of Linde type A zeolite containing calcium ions (Ca-LTA) to an aqueous solution of formaldehyde and glycolaldehyde produced saccharides at room temperature. A quantitative analysis performed by high-performance liquid chromatography revealed that triose, tetrose, pentose, and hexose saccharides were produced with few byproducts. Ca-LTA was recovered from the reaction mixture by filtration, and the retrieved zeolite was found to be reusable under the same conditions. The catalytic activity of Ca-LTA was higher than those of conventional calcium catalysts and other solid materials such as silica, alumina, and hydroxyapatite. Several other types of zeolites with different crystal structures and alkali/alkali-earth metal ions also showed catalytic activity for saccharide formation. Based on the analytical results obtained by infrared spectroscopy, temperature-programmed desorption profiles and NMR measurements, we propose a reaction mechanism in which C-C bond formation is promoted by the mild basicity of the oxygen atoms and acidity on the metal ions of the aluminosilicate on the zeolite surfaces with low SiO2/Al2O3 ratios.

Direct Analysis of Complex Reaction Mixtures: Formose Reaction.

Complex reaction mixtures, like those postulated on early Earth, present an analytical challenge because of the number of components, their similarity, and vastly different concentrations. Interpreting the reaction networks is typically based on simplified or partial data, limiting our insight. We present a new approach based on online monitoring of reaction mixtures formed by the formose reaction by ion-mobility-separation mass-spectrometry. Monitoring the reaction mixtures led to large data sets that we analyzed by non-negative matrix factorization, thereby identifying ion-signal groups capturing the time evolution of the network. The groups comprised ≈300 major ion signals corresponding to sugar-calcium complexes formed during the formose reaction. Multivariate analysis of the kinetic profiles of these complexes provided an overview of the interconnected kinetic processes in the solution, highlighting different pathways for sugar growth and the effects of different initiators on the initial kinetics. Reconstructing the network's topology further, we revealed so far unnoticed fast retro-aldol reaction of ketoses, which significantly affects the initial reaction dynamics. We also detected the onset of sugar-backbone branching for C6 sugars and cyclization reactions starting for C5 sugars. This top-down analytical approach opens a new way to analyze complex dynamic mixtures online with unprecedented coverage and time resolution.

Direct Analysis of Complex Reaction Mixtures: Formose Reaction

AbstractComplex reaction mixtures, like those postulated on early Earth, present an analytical challenge because of the number of components, their similarity, and vastly different concentrations. Interpreting the reaction networks is typically based on simplified or partial data, limiting our insight. We present a new approach based on online monitoring of reaction mixtures formed by the formose reaction by ion‐mobility‐separation mass‐spectrometry. Monitoring the reaction mixtures led to large data sets that we analyzed by non‐negative matrix factorization, thereby identifying ion‐signal groups capturing the time evolution of the network. The groups comprised ≈300 major ion signals corresponding to sugar‐calcium complexes formed during the formose reaction. Multivariate analysis of the kinetic profiles of these complexes provided an overview of the interconnected kinetic processes in the solution, highlighting different pathways for sugar growth and the effects of different initiators on the initial kinetics. Reconstructing the network's topology further, we revealed so far unnoticed fast retro‐aldol reaction of ketoses, which significantly affects the initial reaction dynamics. We also detected the onset of sugar‐backbone branching for C6 sugars and cyclization reactions starting for C5 sugars. This top‐down analytical approach opens a new way to analyze complex dynamic mixtures online with unprecedented coverage and time resolution.

Olivine-catalyzed glycolaldehyde and sugar synthesis under aqueous conditions: Application to prebiotic chemistry

The presence of minerals in the prebiotic environment likely shaped the evolution of organic matter, thereby contributing to the emergence of prebiotic systems. Records of such systems are lacking and the interactions between abiotic organic matter and primary minerals remain poorly understood. Here, we demonstrate the ability of olivine silicates, in simulated early Earth or planetary aqueous environments, to catalyse glycolaldehyde formation from only formaldehyde, and help producing sugars that are essential components for life, through the formose reaction. By combining comprehensive gas chromatography analyses on experimental samples with quantum chemical simulations, we provide a mechanism for an olivine-catalyzed glycolaldehyde formation. Our findings suggest that olivine plays a triple role in the formose chemical network: maintaining an alkaline pH, enabling the initiation step towards the formation of glycoladehyde (which is typically the most challenging step) and promoting the autocatalytic cycle. These results open-up new scenarios on the impact of primary minerals on the evolution of chemical pathways in aqueous environments that were probably essential for the emergence of the first biomolecules.

Spectroscopic FTIR study for pathway of ribose formation via formose reaction in Astrochemistry

Ribose is one of the crucial molecular species in the study of the origin of life as it is the backbone of ribonucleic acid (RNA). On the early Earth, sugars including ribose are thought to be formed through formose reaction. Ribose and other organic molecules were also found in meteorites, signifying their existence in interstellar space, providing them with the essential components for prebiotic chemistry. The formose reaction can produce a mixture of simple sugars from formaldehyde molecules. In our study, we successfully synthesized sugars using the formose reaction under both thermal conditions and microwave irradiation. Notably, sugars were obtained within a remarkably short duration of 1 minute under microwave irradiation. The identification and characterization of the synthesized products were achieved through Fourier transform infrared (FTIR) spectroscopy and Fehling’s test, confirming the successful synthesis of sugars and the presence of aldehyde and alcohol functional groups. In addition, we propose an alternative pathway for sugar synthesis, which holds promise for further exploring the formose reaction in astrochemical experiments.

Prebiotic Synthesis of Glycolaldehyde and Glyceraldehyde from Formaldehyde: A Computational Study on the Initial Steps of the Formose Reaction.

In this work, the initial steps of the mechanism of the Formose reaction (FR) is computationally studied using DFT methods. The FR has been considered to be a relevant process in the prebiotic evolution leading to several types of sugars or carbohydrates. These molecules are some of the basic building blocks of the life. The dimerization of formaldehyde was found to take place via an intramolecular deprotonation reaction, leading to the formation of an intermediate which, after an isomerization, forms a Ca-complex of the cis-enediol tautomer of glycolaldehyde. The aldol reaction of this complex with additional formaldehyde gave glyceraldehyde, the simplest aldotriose. The catalyst Ca(OH)2 plays a dual role in the reaction, acting as a base (in the intramolecular deprotonation) and as Lewis acid (activating the carbonyl group) in the aldol addition.

Carbonyl Migration in Uronates Affords a Potential Prebiotic Pathway for Pentose Production.

Carbohydrate biosynthesis is fundamental to modern terrestrial biochemistry, but how this collection of metabolic pathways originated remains an open question. Prebiotic sugar synthesis has focused primarily on the formose reaction and Kiliani-Fischer homologation; however, how they can transition to extant biochemical pathways has not been studied. Herein, a nonenzymatic pathway for pentose production with similar chemical transformations as those of the pentose phosphate pathway is demonstrated. Starting from a C6 aldonate, namely, gluconate, nonselective chemical oxidation yields a mixture of 2-oxo-, 4-oxo-, 5-oxo-, and 6-oxo-uronate regioisomers. Regardless at which carbinol the oxidation takes place, carbonyl migration enables β-decarboxylation to yield pentoses. In comparison, the pentose phosphate pathway selectively oxidizes 6-phosphogluconate to afford the 3-oxo-uronate derivative, which undergoes facile subsequent β-decarboxylation and carbonyl migration to afford ribose 5-phosphate. The similarities between these two pathways and the potential implications for prebiotic chemistry and protometabolism are discussed.

Metal-Organic Frameworks as Formose Reaction Catalysts with Enhanced Selectivity.

The formose reaction is an autocatalytic series of aldol condensations that allows one to obtain monosaccharides from formaldehyde. The formose reaction suffers from a lack of selectivity, which hinders practical applications at the industrial level. Over the years, many attempts have been made to overcome this selectivity issue, with modest results. Heterogeneous porous catalysts with acid-base properties, such as Metal-Organic Frameworks (MOFs), can offer advantages compared to homogeneous strong bases (e.g., calcium hydroxide) for increasing the selectivity of this important reaction. For the very first time, four different Zeolite Imidazolate Frameworks are presented in this work as catalysts for the formose reaction in liquid phase, and their catalytic performances were compared with those of the typical homogeneous catalyst (i.e., calcium hydroxide). The heterogeneous nature of the catalysis, the possible contribution of leached metal or linkers to the solution, and the stability of the materials were investigated. The porous structure of these solids and their mild basicity make them suitable for obtaining enhanced selectivity at 30% formaldehyde conversion. Most of the MOFs tested showed low structural stability under reaction conditions, thereby indicating the need to search for new MOF families with higher robustness. However, this important result opens the path for future research on porous heterogeneous basic catalysts for the formose reaction.

Synthesis of Carbohydrates from Methanol Using Electrochemical Partial Oxidation over Palladium with the Integrated Formose Reaction

Synthesis of Carbohydrates from Methanol Using Electrochemical Partial Oxidation over Palladium with the Integrated Formose Reaction

Small-molecule autocatalysis drives compartment growth, competition and reproduction.

Sustained autocatalysis coupled to compartment growth and division is a key step in the origin of life, but an experimental demonstration of this phenomenon in an artificial system has previously proven elusive. We show that autocatalytic reactions within compartments-when autocatalysis, and reactant and solvent exchange outpace product exchange-drive osmosis and diffusion, resulting in compartment growth. We demonstrate, using the formose reaction compartmentalized in aqueous droplets in an emulsion, that compartment volume can more than double. Competition for a common reactant (formaldehyde) causes variation in droplet growth rate based on the composition of the surrounding droplets. These growth rate variations are partially transmitted after selective division of the largest droplets by shearing, which converts growth-rate differences into differences in droplet frequency. This shows how a combination of properties of living systems (growth, division, variation, competition, rudimentary heredity and selection) can arise from simple physical-chemical processes and may have paved the way for the emergence of evolution by natural selection.

Comparison of Mono-Ethylene Glycol Prebiotic Synthesis Efficiency via Formose Reaction in Methanol and Water as Solvents: A Short Communication

Comparison of Mono-Ethylene Glycol Prebiotic Synthesis Efficiency via Formose Reaction in Methanol and Water as Solvents: A Short Communication

Serpentinization-Associated Mineral Catalysis of the Protometabolic Formose System.

The formose reaction is a plausible prebiotic chemistry, famed for its production of sugars. In this work, we demonstrate that the Cannizzaro process is the dominant process in the formose reaction under many different conditions, thus necessitating a catalyst for the formose reaction under various environmental circumstances. The investigated formose reactions produce primarily organic acids associated with metabolism, a protometabolic system, and yield very little sugar left over. This is due to many of the acids forming from the degradation and Cannizaro reactions of many of the sugars produced during the formose reaction. We also show the heterogeneous Lewis-acid-based catalysis of the formose reaction by mineral systems associated with serpentinization. The minerals that showed catalytic activity include olivine, serpentinite, and calcium, and magnesium minerals including dolomite, calcite, and our Ca/Mg-chemical gardens. In addition, computational studies were performed for the first step of the formose reaction to investigate the reaction of formaldehyde, to either form methanol and formic acid under a Cannizzaro reaction or to react to form glycolaldehyde. Here, we postulate that serpentinization is therefore the startup process necessary to kick off a simple proto metabolic system-the formose protometabolic system.

Dynamic Environmental Conditions Affect the Composition of a Model Prebiotic Reaction Network.

Prebiotic environments are dynamic, containing a range of periodic and aperiodic variations in reaction conditions. However, the impact of the temporal dynamics of environmental conditions upon prebiotic chemical reaction networks has not been investigated. Here, we demonstrate how the magnitude and rate of temporal fluctuations of the catalysts Ca2+ and hydroxide control the product distributions of the formose reaction. Surprisingly, the product compositions of the formose reaction under dynamic conditions deviate significantly from those under steady state conditions. We attribute these compositional changes to the non-uniform propagation of fluctuations through the network, thereby shaping reaction outcomes. An examination of temporal concentration patterns showed that collections of compounds responded collectively to perturbations, indicating that key gating reactions branching from the Breslow cycle may be important responsive features of the formose reaction. Our findings show how the compositions of prebiotic reaction networks were shaped by sequential environmental events, illustrating the necessity for considering the temporal traits of prebiotic environments that supported the origin of life.

Towards a prebiotic chemoton - nucleotide precursor synthesis driven by the autocatalytic formose reaction.

The formose reaction is often cited as a prebiotic source of sugars and remains one of the most plausible forms of autocatalysis on the early Earth. Herein, we investigated how cyanamide and 2-aminooxazole, molecules proposed to be present on early Earth and precursors for nonenzymatic ribonucleotide synthesis, mediate the formose reaction using HPLC, LC-MS and 1H NMR spectroscopy. Cyanamide was shown to delay the exponential phase of the formose reaction by reacting with formose sugars to form 2-aminooxazole and 2-aminooxazolines thereby diverting some of these sugars from the autocatalytic cycle, which nonetheless remains intact. Masses for tetrose and pentose aminooxazolines, precursors for nucleotide synthesis including TNA and RNA, were also observed. The results of this work in the context of the chemoton model are further discussed. Additionally, we highlight other prebiotically plausible molecules that could have mediated the formose reaction and alternative prebiotic autocatalytic systems.

Construction of an autocatalytic reaction cycle in neutral medium for synthesis of life-sustaining sugars.

Autocatalytic mechanisms in carbon metabolism, such as the Calvin cycle, are responsible for the biological assimilation of CO2 to form organic compounds with complex structures, including sugars. Compounds that form C-C bonds with CO2 are regenerated in these autocatalytic reaction cycles, and the products are concurrently released. The formose reaction in basic aqueous solution has attracted attention as a nonbiological reaction involving an autocatalytic reaction cycle that non-enzymatically synthesizes sugars from the C1 compound formaldehyde. However, formaldehyde and sugars, which are the substrate and products of the formose reaction, respectively, are consumed in Cannizzaro reactions, particularly under basic aqueous conditions, which makes the formose reaction a fragile sugar-production system. Here, we constructed an autocatalytic reaction cycle for sugar synthesis under neutral conditions. We focused on the weak Brønsted basicity of oxometalate anions such as tungstates and molybdates as catalysts, thereby enabling the aldol reaction, retro-aldol reaction, and aldose-ketose transformation, which collectively constitute the autocatalytic reaction cycle. These bases acted on sugar molecules of substrates together with sodium ions of a Lewis acid to promote deprotonation under neutral conditions, which is the initiation step of the reactions forming an autocatalytic cycle, whereas the Cannizzaro reaction was inhibited. The autocatalytic reaction cycle established using this abiotic approach is a robust sugar production system. Furthermore, we found that the synthesized sugars work as energy storage substances that sustain microbial growth despite their absence in nature.

A computational study of the gas-phase interstellar formose-like reactions

Understanding the extraterrestrial origin of ribose, as one of the sub-units of ribonucleic acid (RNA), is crucial to anticipating the formation of the building blocks of life under interstellar medium (ISM) conditions. Under ordinary atmospheric conditions, the formation of sugar is suggested to occur through the formose reaction, where formaldehyde is solely used as the precursor in each of the iterative steps of the formation process. On the other hand, sugar synthesis under ISM conditions has evidently been shown to be significantly different from the terrestrial formose reactions due to the extremely low density of molecules and the very low temperature. In this study, we theoretically investigate the formose-like reactions for ribose formation catalyzed by a single proton through the mean of computer simulation based on first-principles density functional theory (DFT). The ribose formation reactions are modelled in the absence of solvation effects at absolute zero temperature to mimic the extremely low pressure and temperature found in ISM. We observe that the presence of a proton gives rise to a more thermodynamically stable complex of the two reactive carbonyl compounds by bridging their oxygen atoms as required for the iterative formose reaction to proceed. In order to form a new carbon-carbon bond through an iterative process, only the region where the additional formaldehyde attaches to the existed protonated carbonyl compound is of great importance. The energy barriers for all the iterative steps during the ribose formation are similar, i.e., ∼67 kcal mol−1. Our findings show that a single proton can act as an efficient catalyst for the gas-phase ribose formation reactions in the absence of solvent effects. The results also suggest that ribose formation can preferentially occur via the formose pathway in the presence of protons, which are abundantly presented in ISM.

Preferential formation of specific hexose and heptose in the formose reaction under microwave irradiation.

To realize sustainable societies, the production of organic compounds not based on fossil resources should be developed. Thus, C1 chemistry, utilizing one-carbon compounds as starting materials, has been of increasing importance. In particular, the formose reaction is promising because the reaction produces sugars (monosaccharides) from formaldehyde under basic conditions. On the other hand, since microwave (MW) induces the rotational motion of molecules, MW irradiation often improves the selectivity and efficiency of reactions. In this study, the formose reaction under MW irradiation was thus investigated under various conditions. The formose reaction proceeded very fast using 1.0 mol per kg formaldehyde and 55 mmol per kg calcium hydroxide (Ca(OH)2) as a catalyst at a high set temperature (150 °C) for a short time (1 min) to form preferentially specific hexose and heptose. The major products were isolated by thin layer chromatography and characterized by mass spectroscopy and NMR. These characterization data elucidated that the hexose and heptose were 2-hydroxymethyl-1,2,4,5-tetrahydroxy-3-pentanone (C6*) and 2,4-bis(hydroxymethyl)-1,2,4,5-tetrahydroxy-3-pentanone (C7*), respectively. On the basis of these observations, as well as density functional theory calculations, a plausible reaction pathway was also discussed; once 1,3-dihydroxyacetone is formed, consecutive aldol reactions favorably occur to form C6* and C7*.

Soluble Sulfur-Bearing Organic Compounds in Carbonaceous Meteorites: Implications for Chemical Evolution in Primitive Asteroids

Sulfur comprises various compound forms in natural environments and could have played important roles in chemical evolution in the universe. Various soluble organosulfur compounds and inorganic sulfur oxides were identified in the methanol extracts of three carbonaceous chondrites (Murchison, Tagish Lake, and Allende) using high-performance liquid chromatography coupled with high-resolution mass spectrometry. The most abundant S-bearing organic compound was hydroxymethane sulfonic acid (HMSA, HOCH2SO3H), which is reported from a meteorite for the first time, at a concentration of 201 nmol/g in the Murchison meteorite. Because HMSA is known to be produced by the reaction of formaldehyde (HCHO) and bisulfite (HSO3–), this result indicates that formaldehyde should be abundant prior to the reaction with HSO3– in the meteorite parent bodies. The bisulfite derivatives of glycolaldehyde and glyceraldehyde were further identified in the methanol extract, suggesting that the formose reaction had proceeded during the aqueous alteration. The finding of these sugar–HSO3– adducts suggests that the formose reaction might have been controlled by the presence of sulfur species in the body. Furthermore, alkylated sulfonic acids (CnH2n+1SO3H) were also present as a series of homologous compounds up to C14 in the Murchison meteorite, even though previous studies found only C1–C4 sulfonic acids. In addition to organosulfur compounds, variable inorganic polysulfur oxides and acids were detected. The abundant S-bearing compounds in the meteorites imply important roles of sulfur in the organic reactions in carbonaceous asteroids.