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Formose reaction

The Formose reaction, also known as the Butlerov reaction, is an autocatalytic chemical process discovered by Russian chemist Aleksandr Butlerov in 1861, in which formaldehyde polymerizes in an alkaline aqueous solution to form a complex mixture of sugars and polyhydroxy compounds.^[1] This reaction begins with the base-catalyzed dimerization of formaldehyde to glycolaldehyde, followed by a series of aldol condensations, retro-aldol cleavages, and aldose-ketose isomerizations that generate higher-carbon sugars such as glyceraldehyde, erythrose, and ribose, along with branched products and stereoisomers.^[2] The process is highly recursive and non-stereoselective, often yielding a diverse array of aldoses, ketoses, and degradation products like carboxylic acids under standard conditions.^[1] In prebiotic chemistry, the Formose reaction holds significance as a potential abiotic pathway for carbohydrate synthesis on the early Earth, where formaldehyde could have been available from sources like atmospheric photochemistry or volcanic outgassing.^[1] It provides a mechanism for generating the sugars essential for ribonucleotides and metabolic precursors, though challenges such as low yields and instability of products—as well as recent 2025 studies indicating preferential formation of branched sugars over linear ones like ribose under mild prebiotic conditions—have prompted investigations of modified versions, including the silicate-mediated variant that stabilizes sugars and enhances accumulation in aqueous environments with dissolved silicates.^[3]^[4] Despite its messiness and tendency toward side reactions, informed by ongoing research into mechanisms like Cannizzaro dismutation and mineral catalysis, the reaction's autocatalytic nature underscores its relevance to understanding proto-metabolic networks in origins-of-life scenarios.^[1]^[5]^[6]

History

Discovery

The Formose reaction was discovered in 1861 by Russian chemist Alexander Mikhaylovich Butlerov during his investigations into the synthesis of organic substances from simple precursors. In his seminal experiments, Butlerov prepared a solution of formaldehyde—initially in the form of its polymer dioxymethylene, which he had isolated from hexamethylenetetramine—and mixed it with limewater, an aqueous solution of calcium hydroxide (Ca(OH)₂). The mixture was heated under alkaline conditions, leading to a rapid color change in the solution, the emission of a sweet, burnt-sugar odor, and the formation of a viscous, red-brown syrup that he named "formose," derived from "formaldehyde" and the sugar suffix "-ose."^[7]^[8] Butlerov noted that the product was sweet-tasting, much like natural sugars, and formed an insoluble, caramel-like residue upon further processing, consisting of a complex mixture of carbohydrate-like compounds. This observation marked the first documented autocatalytic polymerization of formaldehyde into polyhydroxy compounds, observed as a curiosity in the nascent field of organic synthesis.^[7]^[9] Butlerov interpreted the reaction as a potential artificial mimic of natural sugar formation, suggesting that carbohydrates could arise through the polymerization of formaldehyde or similar simple molecules under basic conditions, challenging prevailing views that organic compounds like sugars could only be produced biologically. This insight predated the modern mechanistic understanding of aldol condensations—key to the reaction's propagation—which were not formally described until the 1870s.^[7]^[8]^[10]

Key developments

In the mid-20th century, researchers advanced the understanding of the Formose reaction through detailed product analysis and mechanistic insights. During the 1950s, H. S. Isbell and colleagues employed paper chromatography to identify specific aldoses among the reaction products, including ribose and arabinose, marking a significant step in characterizing the mixture's composition.^[11] A pivotal contribution came in 1959 when Ronald Breslow elucidated the reaction's mechanism, proposing that glycolaldehyde serves as a crucial intermediate formed from formaldehyde via an acyloin-type condensation, which then autocatalytically drives subsequent aldol additions.^[12] The 1960s saw experiments exploring mineral-based catalysis to enhance control and stability. Studies demonstrated that minerals such as kaolin and calcium carbonate could facilitate the reaction under milder conditions, reducing product degradation and favoring the formation of higher sugars.^[13] In 1967, N. W. Gabel and C. Ponnamperuma reported that borate ions inhibit excessive polymerization by forming complexes with dihydroxyacetone and glyceraldehyde, thereby stabilizing pentoses like ribose for potential prebiotic scenarios.^[14] By the 1970s, investigations into phosphate's role highlighted its potential to modulate the reaction pathway, with inorganic phosphates promoting the phosphorylation of intermediates and shifting yields toward biologically relevant sugar phosphates, underscoring the reaction's implications for early Earth chemistry.^[15]

Reaction overview

Description

The Formose reaction is a complex, autocatalytic process that transforms formaldehyde into a diverse array of carbohydrate-like compounds under alkaline conditions.^[16] Discovered by Russian chemist Aleksandr Butlerov in 1861, it provides a model for abiotic synthesis of sugars and has implications for prebiotic chemistry.^[8] The primary input is formaldehyde (\ce{HCHO}) in an aqueous medium with alkaline catalysis, typically involving a base such as hydroxide ions (\ce{OH^-}).^[16] The overall process can be simplified by the equation

n \ce{HCHO} \xrightarrow{\ce{OH^-}} (\ce{CH2O})_n

which represents the polymerization of formaldehyde units into higher-carbon structures.^[17] The outputs consist of a mixture of polyhydroxy aldehydes (aldoses) and ketones (ketoses)—collectively resembling sugars—with carbon chain lengths ranging from C₂ to C₈, alongside polymeric "formose" material that forms as a brownish residue.^[18] ^[19] This reaction is classified as an autocatalytic chain of aldol condensations, where formaldehyde units are sequentially incorporated to build branched, carbohydrate-like architectures.^[17] A key feature of its autocatalysis is the role of glycolaldehyde (a C₂ product) as an initiator, which facilitates the rapid addition of further formaldehyde molecules and sustains the reaction's progression.^[17]

Conditions and catalysis

The Formose reaction is typically performed in an aqueous medium, where formaldehyde serves as the primary substrate at concentrations ranging from 0.1 to 2 M.^[20] The reaction proceeds under strongly alkaline conditions, with a pH of 12–14 achieved using bases such as calcium hydroxide (Ca(OH)₂) or sodium hydroxide (NaOH) at 0.1–1 M concentrations.^[20]^[21] These hydroxide ions (OH⁻) act as the primary catalyst, facilitating the autocatalytic aldol condensations central to the process.^[20] Temperatures for the reaction are generally maintained between 20 and 60 °C to control the rate and prevent excessive side reactions, though higher temperatures up to 90 °C have been employed in some setups.^[20] Reaction durations typically span 30 minutes to several hours, often until the formaldehyde is substantially depleted, with stirring in open vessels to ensure homogeneity.^[20]^[21] An inert atmosphere, such as nitrogen, may be used optionally to limit oxidation of intermediates.^[21] Beyond hydroxide catalysis, alternative systems have been developed to improve control and selectivity. Thiazolium salts, inspired by enzyme active sites like those in transketolase, serve as organocatalysts at millimolar levels.^[20] Divalent metal ions, particularly Ca²⁺ from Ca(OH)₂, provide additional Lewis acid assistance, while other options include borates, silicates, or phosphates at 40–80 mM.^[20] More recently, heterogeneous catalysts such as metal-organic frameworks (e.g., ZIF-8 and ZIF-67) have been applied at loadings of 20 mg per mL, enabling reactions at 50–60 °C over 24 hours.^[21] Water remains the standard solvent, but modifications involving co-solvents like methanol or 1,4-dioxane, or additives such as salts, can influence the reaction kinetics and intermediate stability without altering the core aqueous environment.^[20]

Mechanism

Initiation

The initiation of the Formose reaction begins under basic conditions, where formaldehyde (HCHO), typically in its hydrated form H₂C(OH)₂ in aqueous solution, can follow different pathways. In the classical view, it undergoes deprotonation by hydroxide ions (OH⁻) to generate an enolate-like intermediate H₂C(OH)O⁻, which serves as a nucleophile. However, deuterium labeling studies reveal a revised mechanism involving hydride shifts: the initial C–C bond formation occurs when one formaldehyde adds to another, with a hydride transferred from the attacking unit to the attacked unit, followed by protonation from water to yield glycolaldehyde (HOCH₂CHO).^[2]^[1] In the absence of suitable initiators or impurities, pure formaldehyde solutions under basic catalysis predominantly follow the Cannizzaro reaction pathway, a disproportionation that yields methanol (CH₃OH) and formate (HCOO⁻) rather than carbon-carbon bond formation. However, trace impurities, such as glycolaldehyde or other aldehydes, or even minute autocatalytic effects can divert the reaction toward the aldol pathway with hydride involvement, enabling the formation of the key initial product, glycolaldehyde. The net reaction for this step is:

\mathrm{HCHO + HCHO + OH^- \rightarrow HOCH_2CHO + H_2O}

This process is catalyzed by the base and represents the slow, rate-limiting initiation phase of the Formose reaction.^[22]^[1] Once formed, glycolaldehyde contributes to autocatalysis by undergoing deprotonation to produce an enediolate intermediate, which enhances the rate of further formaldehyde additions, potentially involving hydride transfers. This enediolate form accelerates the consumption of formaldehyde, marking the transition from initiation to subsequent propagation.^[22]^[2]

Propagation and termination

The propagation phase of the Formose reaction involves the repeated addition of formaldehyde to intermediates derived from initial products like glycolaldehyde, leading to the formation of longer-chain aldoses and ketoses through aldol condensations that incorporate hydride shifts.^[23] For instance, glycolaldehyde reacts with formaldehyde to produce glyceraldehyde, with the mechanism involving hydride transfer during C-C bond formation:

\ce{HOCH2CHO + HCHO ->[OH^-] HOCH2CH(OH)CHO}

This step exemplifies the chain elongation, where the growing unit facilitates hydride shift to the formaldehyde carbonyl, followed by protonation to yield the aldose product.^[2] Subsequent iterations extend the carbon chain, generating trioses, tetroses, pentoses, and higher sugars, with the process becoming autocatalytic as product sugars revert to enediol forms that catalyze further condensations, often via hydride-mediated pathways.^[23] Branching arises during propagation when aldoses isomerize to ketoses via intermediates, diversifying the product mixture with stereoisomers. A key example is the conversion of glyceraldehyde to dihydroxyacetone (a ketose), where deuterium studies indicate hydride shifts, potentially with quantum tunneling, shift the carbonyl group:

\ce{HOCH2CH(OH)CHO ->[OH^-] [intermediate] -> HOCH2COCH2OH}

This isomerization enables crossed aldol reactions, such as dihydroxyacetone adding formaldehyde to form branched ketoses like erythrulose, contributing to the exponential growth of structural variants up to heptoses and beyond.^[2]^[1] The autocatalytic feedback sustains propagation until formaldehyde depletion, with higher sugars continuously breaking down to active species.^[23] Termination occurs as higher sugars undergo dehydration and oxidation, forming polymeric tars known as formosans, which precipitate as brown, chromophoric materials.^[1] These processes involve retro-aldol cleavages and Cannizzaro disproportionations that degrade monosaccharides into carboxylic acids (e.g., glycolic and lactic acid) and insoluble polymers, with less than 1% of initial formaldehyde incorporating into stable sugars.^[23] The reaction enters a degradation phase marked by yellowing and tar formation, halting net sugar production.^[1]

Products

Composition

The Formose reaction generates a diverse array of carbohydrate products from formaldehyde under alkaline conditions, primarily consisting of low-molecular-weight aldoses and ketoses. Key primary products include the C2 aldose glycolaldehyde (HOCH₂CH(OH)CHO), the C3 aldose glyceraldehyde (HOCH₂CH(OH)CH(OH)CHO), the C4 aldose erythrose (HOCH₂(CHOH)₂CHO), and the C5 aldose ribose (HOCH₂(CHOH)₃CHO), alongside ketoses such as the C3 dihydroxyacetone (HOCH₂COCH₂OH) and the C6 fructose (HOCH₂(CHOH)₃COCH₂OH). In addition to sugars, the reaction produces substantial amounts of organic acids (e.g., formic, lactic, glycolic) and alcohols (e.g., ethylene glycol, glycerol), often comprising the majority of converted formaldehyde.^[8] These molecules form through successive aldol condensations, with glycolaldehyde serving as the initial autocatalyst.^[8]^[20] In the early stages of the reaction, C2 and C3 products dominate the composition, with glycolaldehyde accumulating as the dominant product before further elongation occurs. As the reaction progresses, higher sugars become prominent, but monomeric yields remain low, typically <10% of the converted formaldehyde under standard conditions (e.g., 0.5-2 M formaldehyde, Ca(OH)₂ catalysis at 40-80°C), due to side reactions and polymerization.^[24]^[20] The sugar products are formed as racemic mixtures, lacking stereoselectivity in the absence of chiral catalysts; for instance, D- and L-ribose together constitute approximately 1-5% of the pentose products in uncontrolled reactions. A substantial polymeric fraction, known as insoluble formose or "browning tar," arises from cross-linking and dehydration of the aldoses. This polymer is a complex network of polyaldoses with aliphatic, furanic, and carbonyl functionalities. Formaldehyde conversion efficiency exceeds 90% in most setups, but effective isolation of monomeric sugars is limited without modifications like borate or phosphate additives.^[8]^[25]^[20]

Analysis and characterization

The analysis and characterization of products from the Formose reaction have advanced significantly since its discovery, transitioning from rudimentary qualitative assessments to precise instrumental techniques that enable identification, quantification, and structural elucidation of the complex mixture of sugars and related compounds produced.^[8] Initially, in 1861, Aleksandr Butlerov described the reaction's output as a viscous, sweet-tasting yellow syrup, inferring the presence of carbohydrate-like substances through sensory evaluation and solubility tests in water and alcohol, marking the earliest form of product characterization.^[8] By the mid-20th century, as the reaction gained attention for prebiotic implications, more systematic methods emerged to handle the diverse monosaccharides, including aldoses and ketoses ranging from C3 to higher oligomers. Chromatographic techniques have been pivotal for separating and identifying individual sugars in the Formose mixture, which often comprises over 40 compounds. In the 1950s, paper chromatography was widely adopted to resolve sugars based on their retention factors (Rf values), allowing detection of specific components like ribose through visualization with silver nitrate or aniline phthalate sprays.^[26] Modern refinements include high-performance liquid chromatography (HPLC), often coupled with ultraviolet (UV) detection after derivatization (e.g., with 2,4-dinitrophenylhydrazine), to quantify sum parameters like total aldoses and ketoses with high accuracy and minimal interference from formaldehyde.^[27] Gas chromatography-mass spectrometry (GC-MS), typically following trimethylsilylation derivatization, excels at resolving stereoisomers, such as the eight hexose diastereomers, and has revealed preferential formation of pentoses (up to 65% of products) under certain modified conditions, such as in lipid vesicles.^[20] Spectroscopic methods provide structural confirmation without extensive sample preparation, complementing chromatography for the reaction's polyhydroxylated products. Nuclear magnetic resonance (NMR) spectroscopy, particularly ¹H NMR, identifies aldose protons in the 3.5–4.5 ppm range and has been used to verify the formation of glycolaldehyde and higher sugars in catalyzed variants, such as those in borate buffers yielding isotopically labeled ribose. Infrared (IR) spectroscopy detects characteristic carbonyl stretches (around 1700–1750 cm⁻¹ for aldoses and ketoses) and hydroxyl bands (3200–3600 cm⁻¹), aiding pathway studies like ribose synthesis via Fourier-transform IR (FTIR) analysis of intermediates in astrochemically relevant conditions.^[28] Mass spectrometry offers insights into molecular weight distributions, especially for polymeric or complex Formose products. Electrospray ionization-mass spectrometry (ESI-MS) has been employed to profile monomeric sugars (C3–C8) and calcium-sugar complexes in real-time, revealing dynamic oligomer growth during the reaction.^[29] When integrated with ion-mobility separation, ESI-MS distinguishes isobaric species, enhancing characterization of the reaction's emergent behaviors. Enzymatic assays enable selective quantification of active monomers by leveraging sugar-specific enzymes, providing functional validation beyond structural data. For instance, glycerol dehydrogenase coupled with NADH monitoring quantifies glycolaldehyde and dihydroxyacetone, key early products, while engineered aldolases (e.g., formolase variants) process Formose outputs to confirm substrate compatibility and yield C3–C6 sugars with high specificity.^[30] These methods, often combined (e.g., LC-ESI-MS or GC-MS post-enzymatic treatment), underscore the reaction's complexity and facilitate targeted studies of its product diversity.

Significance

Prebiotic chemistry

The Formose reaction has been proposed as a key process in prebiotic carbohydrate synthesis, where formaldehyde (HCHO), generated through the reduction of CO or formic acid by H₂ in hydrothermal vents, undergoes polymerization under alkaline conditions. This formaldehyde could accumulate in environments such as alkaline hydrothermal vents or evaporating ponds on early Earth, where base catalysis would drive the autocondensation to form sugars. In hydrothermal vents, formaldehyde formation via the reduction of CO or formic acid by H₂ provides a continuous supply, with the reaction proceeding plausibly at moderate hydrothermal temperatures, potentially yielding glycolaldehyde and higher saccharides before significant degradation occurs.^[31] The reaction's relevance to the RNA world hypothesis lies in its potential to produce ribose, the sugar component of RNA nucleotides, from simple precursors.^[8] Extensions of the 1950s Miller-Urey experiments, which simulated early Earth's reducing atmosphere and produced formic acid reducible to formaldehyde, incorporated Formose-like conditions to generate sugar mixtures, supporting the idea that abiotic carbohydrate synthesis could precede nucleic acid formation. In geological contexts, minerals such as clays (e.g., kaolinite) and borates catalyze and stabilize the reaction; for instance, borate minerals selectively stabilize ribose against degradation in Formose mixtures, enhancing its availability for prebiotic nucleotide assembly.^[32] Similarly, polyaromatic hydrocarbons in carbonaceous meteorites like Murchison contain sugars, including ribose and arabinose, suggestive of Formose-like processes occurring extraterrestrially or during atmospheric entry. Despite these advantages, the Formose reaction typically yields low concentrations of pentoses like ribose amid a complex mixture of products, posing a selectivity challenge for prebiotic scenarios.^[33] However, wet-dry cycles in shallow ponds could concentrate formaldehyde and intermediates, promoting higher sugar formation through repeated evaporation and rehydration.^[34] Phosphate has been suggested to influence sugar yields and stability in the reaction, offering a potential mechanism in phosphate-rich prebiotic settings. Recent studies as of 2025 have questioned the efficiency of the standard Formose reaction for direct ribose production, proposing alternative non-enzymatic pathways under controlled conditions.^[35]

Modern applications

In synthetic carbohydrate production, controlled variants of the Formose reaction enable the generation of isotopically labeled sugars for use in biochemical and metabolic studies. By starting with ¹³C-labeled formaldehyde, the reaction yields carbohydrates that can be tracked through mass spectrometry or NMR spectroscopy to elucidate reaction pathways or biological processes. For instance, ¹³C-formaldehyde has been employed to produce labeled glycolaldehyde and higher sugars, facilitating detailed mechanistic investigations and applications in tracer studies. Biotechnological applications leverage enzyme-mimicking catalysts inspired by the Formose reaction to promote sustainable, selective synthesis in green chemistry. Researchers have engineered a retro-aldolase enzyme, termed formolase, through computational design and directed evolution to catalyze the key dimerization of formaldehyde to glycolaldehyde under mild aqueous conditions. This biocatalyst achieves turnover numbers up to 3 min⁻¹ and offers potential for scalable production of simple sugars without the uncontrolled branching typical of the uncatalyzed reaction, aligning with eco-friendly manufacturing goals.^[36] Recent advances in the 2010s and 2020s have focused on reactor technologies and novel catalysts to enhance selectivity and yield for specific sugars like pentoses. Microfluidic reactors provide precise control over residence time and mixing, enabling continuous-flow synthesis of hexoses such as glucose and fructose from formaldehyde with improved efficiency over batch methods. In parallel, 2020s developments include metal-organic frameworks (MOFs) as heterogeneous catalysts, which promote carbohydrate formation from formaldehyde at 60°C, achieving up to 80% conversion with around 50% selectivity to trioses while minimizing degradation products. These innovations support targeted pentose production for research applications.^[37]^[21] The Formose reaction holds industrial potential as a low-cost pathway to platform chemicals and biofuels from syngas-derived formaldehyde. A linked process integrates Formose triose formation with aqueous-phase reforming and hydrogenation to convert carbohydrates into liquid fuels like 2,4-dimethylfuran (yield ~50%) or C₉-C₁₅ alkanes, bypassing energy-intensive biomass pretreatment steps. However, challenges in selectivity and product separation limit current scalability, though optimized conditions achieve 96% selectivity to dihydroxyacetone as a glycerol precursor.^[38]

Challenges and variations

Limitations

The Formose reaction exhibits low selectivity, rapidly generating a diverse array of carbohydrate isomers, branched structures, and higher oligomers from formaldehyde under alkaline conditions, resulting in pentoses comprising less than 5% of the products.^[8] This lack of specificity arises from the autocatalytic nature of the process, where initial aldol condensations propagate uncontrollably, favoring a complex mixture over targeted monosaccharides.^[39] The sugars produced are inherently unstable, particularly at the high pH typically required for the reaction, leading to degradation through retro-aldol cleavages that revert aldoses and ketoses to smaller fragments like formaldehyde and glycolaldehyde.^[8] This non-productive pathway dominates under standard conditions, reducing overall efficiency and complicating downstream isolation. Competing side reactions exacerbate these issues, with the Cannizzaro disproportionation of formaldehyde producing formate and methanol, thereby diverting a significant portion of the starting material away from sugar formation.^[20] Scalability poses additional challenges, as the highly exothermic and autocatalytic progression can lead to thermal runaway, promoting uncontrolled polymerization and the formation of tarry precipitates that encapsulate monomeric sugars.^[19] Moreover, sensitivity to ultraviolet light induces branching reactions, further diversifying the product slate and yielding non-linear polyols incompatible with biological pathways.^[20] A large majority of the material ends up as unusable polymeric tar or side products, with only trace amounts of soluble sugars persisting before degradation.^[8] This quantitative imbalance underscores the reaction's impracticality for selective synthesis without intervention. A 2025 study suggests that under controlled prebiotic conditions, the Formose reaction predominantly yields branched-chain sugars rather than linear ones like ribose, challenging its role in abiotic sugar synthesis.^[40]

Modifications

To address the challenges of product instability and low selectivity in the Formose reaction, various modifications have been developed to stabilize key intermediates, particularly pentoses like ribose, and to enhance control over the reaction pathway. One prominent strategy involves the addition of inhibitors such as borate or phosphate ions, which form complexes that prevent degradation of sugars. Borate minerals, for instance, selectively stabilize ribose by forming borate-ribose complexes, allowing its accumulation amid the typically destructive mixture of products; in experiments with borate supplementation, ribose yields can reach up to 60% of total pentoses under prebiotic-like conditions. Similarly, soluble phosphates like acetyl phosphate halt the reaction progression by precipitating calcium as minerals such as apatite, thereby preserving pentoses including ribose at approximately 10-fold higher levels compared to unmodified runs after several hours. These additives not only boost the yield of target sugars but also mimic geochemical environments where such ions could have concentrated on early Earth.^[41]^[42] Another approach employs templating agents, such as minerals or nucleotides, to influence product distribution and potentially induce stereoselectivity. Montmorillonite clay, a layered silicate mineral, serves as a heterogeneous catalyst that enhances selectivity toward specific aldoses like glyceraldehyde by adsorbing formaldehyde and intermediates on its surface, with optimal effects observed at pH around 8.7 where glyceraldehyde production is favored over broader polyol formation. Nucleotides can act as templates in related prebiotic systems, directing the assembly of chiral sugars through hydrogen bonding and steric constraints, though direct application to the Formose reaction remains exploratory. These templating methods leverage surface catalysis to promote ordered growth, reducing the randomness inherent to the uncatalyzed process.^[43] Process modifications, including sequential addition of formaldehyde, further enable control by favoring monomeric and low-molecular-weight products over extensive polymerization. By slowly feeding formaldehyde into the reaction mixture—typically at rates that maintain low concentrations (e.g., below 100 mM)—the autocatalytic acceleration is tempered, allowing isolation of trioses like glyceraldehyde and dihydroxyacetone while minimizing higher sugar formation and tar buildup. This technique, often implemented in continuous-flow setups, has been shown to increase the proportion of monomers by limiting the availability of the Cannizzaro-sensitive initiator glycolaldehyde.^[17] Alternative catalysts offer pathways for asymmetric synthesis and initiation under milder conditions. Organocatalysts derived from proline, such as (S)-proline tetrazoles, promote enantioselective aldol condensations in Formose-like reactions of glycolaldehyde, yielding chiral tetroses with high enantiomeric excess (up to 90% ee) under potentially prebiotic aqueous conditions. Photochemical variants utilize UV irradiation (e.g., 254 nm) to initiate the reaction without bases, generating hydrated electrons via cyanocuprate photoredox cycles that convert HCN or formaldehyde to selective C2-C3 sugars like glycolaldehyde and glyceraldehyde, bypassing the unselective thermal pathway.^[44] Recent innovations in the 2020s include low-temperature variants, termed cryo-Formose, conducted near 0°C or below to slow kinetics and isolate reactive intermediates for detailed mechanistic study; these conditions favor smaller monosaccharides and enable spectroscopic trapping of enediolates that rapidly evolve at ambient temperatures. Enzymatic hybrids integrate computationally designed enzymes like formolase (FLS), an evolved retro-aldolase variant, with the Formose network to achieve precise C-C bond formation; FLS catalyzes formaldehyde dimerization to glycolaldehyde and dihydroxyacetone with tunable product ratios based on substrate concentration, offering >100-fold rate enhancements over abiotic processes and enabling hybrid cascades for sustainable carbon fixation. These advancements collectively transform the Formose reaction from a chaotic process into a tunable synthetic tool.^[20]^[9]

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