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Hydroxymethylfurfural
Hydroxymethylfurfural
Hydroxymethylfurfural
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Hydroxymethylfurfural
Structural formula of hydroxymethylfurfural
Hydroxymethylfurfural
Ball-and-stick model of the hydroxymethylfurfural molecule
Space-filling model of the hydroxymethylfurfural molecule
Names
Preferred IUPAC name
5-(Hydroxymethyl)furan-2-carbaldehyde[1]
Other names
5-(Hydroxymethyl)-2-furaldehyde[1]
5-(Hydroxymethyl)furfural[1]
Identifiers
3D model (JSmol)
110889
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.595 Edit this at Wikidata
EC Number
  • 200-654-9
278693
KEGG
UNII
  • InChI=1S/C6H6O3/c7-3-5-1-2-6(4-8)9-5/h1-3,8H,4H2 checkY
    Key: NOEGNKMFWQHSLB-UHFFFAOYSA-N checkY
  • InChI=1/C6H6O3/c7-3-5-1-2-6(4-8)9-5/h1-3,8H,4H2
    Key: NOEGNKMFWQHSLB-UHFFFAOYAB
  • c1cc(oc1CO)C=O
Properties
C6H6O3
Molar mass 126.111 g·mol−1
Appearance Low melting white solid
Odor Buttery, caramel
Density 1.29 g/cm3
Melting point 30 to 34 °C (86 to 93 °F; 303 to 307 K)
Boiling point 114 to 116 °C (237 to 241 °F; 387 to 389 K) (1 mbar)
UV-vis (λmax) 284 nm[2]
Related compounds
Related furan-2-carbaldehydes
 Furfural

Methoxymethylfurfural

Hazards
GHS labelling:
GHS07: Exclamation mark[3]
Warning[3]
H315, H319, H335[3]
P261, P305+P351+P338, P310[3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Hydroxymethylfurfural (HMF), also known as 5-(hydroxymethyl)furfural, is an organic compound formed by the dehydration of reducing sugars.[4][5] It is a white low-melting solid (although commercial samples are often yellow) which is highly soluble in both water and organic solvents. The molecule consists of a furan ring, containing both aldehyde and alcohol functional groups.

HMF can form in sugar-containing food, particularly as a result of heating or cooking. Its formation has been the topic of significant study as HMF was regarded as being potentially carcinogenic to humans. However, so far in vivo genotoxicity was negative. No relevance for humans concerning carcinogenic and genotoxic effects can be derived.[6] HMF is classified as a food improvement agent [7] and is primarily being used in the food industry in form of a food additive as a biomarker as well as a flavoring agent for food products.[8][9] It is also produced industrially on a modest scale[10] as a carbon-neutral feedstock for the production of fuels[11] and other chemicals.[12]

Production and reactions

[edit]

HMF was first reported in 1875 as an intermediate in the formation of levulinic acid from sugar and sulfuric acid.[13] This remains the classical route, with 6-carbon sugars (hexoses) such as fructose undergoing acid catalyzed poly-dehydration.[14][15] When hydrochloric acid is used 5-chloromethylfurfural is produced instead of HMF. Similar chemistry is seen with 5-carbon sugars (pentoses), which react with aqueous acid to form furfural.

fructopyranose 1, fructofuranose 2, two intermediate stages of dehydration (not isolated) 3,4 and finally HMF 5

The classical approach tends to suffer from poor yields as HMF continues to react in aqueous acid, forming levulinic acid.[4] As sugar is not generally soluble in solvents other than water, the development of high-yielding reactions has been slow and difficult; hence while furfural has been produced on a large scale since the 1920s,[16] HMF was not produced on a commercial scale until over 90 years later. The first production plant coming online in 2013.[10] Numerous synthetic technologies have been developed, including the use of ionic liquids,[17][18] continuous liquid-liquid extraction, reactive distillation and solid acid catalysts to either remove the HMF before it reacts further or to otherwise promote its formation and inhibit its decomposition.[19]

Derivatives

[edit]

HMF itself has few applications. It can however be converted into other more useful compounds.[12] Of these the most important is 2,5-furandicarboxylic acid, which has been proposed as a replacement for terephthalic acid in the production of polyesters.[20][21] HMF can be converted to 2,5-dimethylfuran (DMF), a liquid that is a potential biofuel with a greater energy content than bioethanol. Hydrogenation of HMF gives 2,5-bis(hydroxymethyl)furan. Acid-catalysed hydrolysis converts HMF into gamma-hydroxyvaleric acid and gamma-valerolactone, with loss of formic acid.[5][4]

Occurrence in food

[edit]

HMF is practically absent in fresh food, but it is naturally generated in sugar-containing food during heat-treatments like drying or cooking. Along with many other flavor- and color-related substances, HMF is formed in the Maillard reaction as well as during caramelization. In these foods it is also slowly generated during storage. Acid conditions favour generation of HMF.[22] HMF is a well known component of baked goods. Upon toasting bread, the amount increases from 14.8 (5 min.) to 2024.8 mg/kg (60 min).[5] It is also formed during coffee roasting, with up to 769 mg/kg.[23]

It is a good wine storage time−temperature marker,[24] especially in sweet wines such as Madeira[25] and those sweetened with grape concentrate arrope.[26]

Phallus indusiatus. Cooktown, Queensland, Australia. The fruiting body contains hydroxymethylfurfural.

HMF can be found in low amounts in honey, fruit-juices and UHT-milk. Here, as well as in vinegars, jams, alcoholic products or biscuits, HMF can be used as an indicator for excess heat-treatment. For instance, fresh honey contains less than 15 mg/kg—depending on pH-value and temperature and age,[27] and the codex alimentarius standard requires that honey have less than 40 mg/kg HMF to guarantee that the honey has not undergone heating during processing, except for tropical honeys which must be below 80 mg/kg.[28]

Higher quantities of HMF are found naturally in coffee and dried fruit. Several types of roasted coffee contained between 300 – 2900 mg/kg HMF.[29] Dried plums were found to contain up to 2200 mg/kg HMF. In dark beer 13.3 mg/kg were found,[30] bakery-products contained between 4.1 – 151 mg/kg HMF.[31]

It can be found in glucose syrup.

HMF can form in high-fructose corn syrup (HFCS), levels around 20 mg/kg HMF were found, increasing during storage or heating.[27] This is a problem for American beekeepers because they use HFCS as a source of sugar when there are not enough nectar sources to feed honeybees, and HMF is toxic to them. Adding bases such as soda ash or potash to neutralize the HFCS slows the formation of HMF.[27]

Depending on production-technology and storage, levels in food vary considerably. To evaluate the contribution of a food to HMF intake, its consumption-pattern has to be considered. Coffee is the food that has a very high relevance in terms of levels of HMF and quantities consumed.

HMF is a natural component in heated food but usually present in low concentrations. The daily intake of HMF may underlie high variations due to individual consumption-patterns. It has been estimated that the intakes range between 4 mg - 30 mg per person per day, while an intake of up to 350 mg can result from, e.g., beverages made from dried plums.[6][32]

Biomedical

[edit]

A major metabolite in humans is 5-hydroxymethyl-2-furoic acid (HMFA), also known as Sumiki's acid, which is excreted in urine.

HMF bind intracellular sickle hemoglobin (HbS). Preliminary in vivo studies using transgenic sickle mice showed that orally administered 5HMF inhibits the formation of sickled cells in the blood.[33] Under the development code Aes-103, HMF has been considered for the treatment of sickle cell disease.[34]

Quantification

[edit]

Today, HPLC with UV-detection is the reference-method (e.g. DIN 10751–3). Classic methods for the quantification of HMF in food use photometry. The method according to White is a differential UV-photometry with and without sodium bisulfite-reduction of HMF.[35] Winkler photometric method is a colour-reaction using p-toluidine and barbituric acid (DIN 10751–1). Photometric test may be unspecific as they may detect also related substances, leading to higher results than HPLC-measurements. Test-kits for rapid analyses are also available (e.g. Reflectoquant HMF, Merck KGaA).[36][37]

Other

[edit]

HMF is an intermediate in the titration of hexoses in the Molisch's test. In the related Bial's test for pentoses, the hydroxymethylfurfural from hexoses may give a muddy-brown or gray solution, but this is easily distinguishable from the green color of pentoses.

Acetoxymethyl furfural (AMF) is also bio-derived green platform chemicals as an alternative to HMF.[38]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Hydroxymethylfurfural

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from Grokipedia
5-Hydroxymethylfurfural (HMF), chemically known as 5-(hydroxymethyl)-2-furaldehyde, is an with the molecular formula C₆H₆O₃ and a molecular weight of 126.11 g/mol. It features a ring substituted at the 2-position with a formyl group (-CHO) and at the 5-position with a (-CH₂OH). HMF appears as a to solid with a of 31.5–35 °C and a of 114–116 °C at 1 mm Hg, and it is soluble in organic solvents such as , , and acetone. This compound serves as a key intermediate in and is recognized for its role in the and processes during food heating. HMF forms naturally through the acid-catalyzed of sugars, such as and glucose, particularly under conditions of high temperature and low (below 4). It is commonly detected in processed foods like , , baked goods, dried fruits, and , where levels can indicate the extent of , with concentrations often exceeding 120°C leading to its accumulation. In , HMF arises from the breakdown of reducing sugars in acidic environments and serves as a quality marker, with regulatory limits set at 40 mg/kg for general honey and 80 mg/kg for tropical types to ensure freshness. Additionally, HMF appears in solutions, cigarette smoke, and roasted products like chestnuts and bread. Industrially, HMF is produced via the of biomass-derived carbohydrates, achieving yields up to 90% using catalysts like ion-exchange resins in solvents such as DMSO or water. It is commercially available at 95–99% purity from suppliers and acts as a versatile platform chemical for and materials. Key derivatives include oxidation products like 2,5-furandicarboxylic acid (FDCA) for polyesters and polyamides, and reduction products like 2,5-bis(hydroxymethyl) for polymers. HMF also finds applications in synthesizing pharmaceuticals, , corrosion inhibitors, and resins, positioning it as a bridge between and high-value chemicals. Regarding safety, HMF is an irritant to the eyes, , and , with an acute oral LD50 of 3.1 g/kg in rats. While dietary intake is estimated at 30–150 mg/person/day and it is rapidly metabolized and excreted in urine as 5-hydroxymethyl-2-furoic acid, high doses show mutagenic potential and possible promotion of colon cancer in animal models. No carcinogenicity was observed in rats, but some evidence exists in female mice for hepatocellular adenomas.

Chemical properties

Molecular structure

Hydroxymethylfurfural (HMF), with the molecular formula C6H6O3, has a molecular weight of 126.11 g/mol. The IUPAC name for HMF is 5-(hydroxymethyl)furan-2-carbaldehyde, reflecting its core ring substituted with an group at the 2-position and a at the 5-position. Common synonyms include 5-hydroxymethylfurfural and 5-hydroxymethyl-2-furaldehyde, the latter emphasizing the furan-2-carbaldehyde backbone. Structurally, HMF features a planar five-membered heterocycle, consisting of four carbon atoms and one oxygen atom, with alternating s conferring aromatic character. The functional group (-CHO) is attached to carbon 2 adjacent to the oxygen, while the (-CH2OH) is bonded to carbon 5, opposite the oxygen in the ring. This arrangement can be textually represented as:

O / \ C C-CHO | | C==C-CH2OH

O / \ C C-CHO | | C==C-CH2OH

where the ring is denoted with the oxygen at the top, between carbons 3 and 4, and substituents at positions 2 and 5. The positioning of these electron-withdrawing and polar groups influences the molecule's reactivity, particularly at the functional groups.

Physical and chemical properties

Hydroxymethylfurfural (HMF) appears as a colorless to pale yellow crystalline solid, often in needle-like form. It has a low of 30–34 °C and a of 1.243 g/mL at 25 °C. Under (1 mmHg), HMF boils at 114–116 °C, but at , it decomposes around 240–250 °C without a defined . HMF is highly soluble in water and polar solvents such as , , acetone, , and , with solubility in exceeding 10 g/100 mL at ; it shows low solubility in non-polar solvents like and . The compound is hygroscopic, light-sensitive, and prone to oxidation in air or during storage, heating, or exposure to light, which can lead to decomposition and emission of irritating fumes. The pKa of the hydroxymethyl (alcohol) group is approximately 13.65, indicating weak acidity typical of primary alcohols, while the aldehyde group does not exhibit significant acidity under standard conditions. In UV-Vis spectroscopy, HMF displays a maximum absorption at 284 nm, attributed to the π–π* transition in its conjugated furan-aldehyde system. reveals characteristic bands, including the carbonyl (C=O) stretch of the aldehyde at approximately 1700 cm⁻¹ (conjugated and lowered from typical aldehydic values) and a broad O–H stretch around 3200–3600 cm⁻¹ due to hydrogen bonding. As a bifunctional with an and a attached to the ring, HMF facilitates hydrogen bonding and exhibits reactivity influenced by these groups, enabling its role in various chemical transformations while maintaining stability under neutral, anhydrous conditions.

Synthesis

From carbohydrates

Hydroxymethylfurfural (HMF) was first isolated in 1895 during studies on sugar , with Kiermayer reporting its preparation from under acidic conditions. Independently, in the same year, Dull obtained HMF from levulose (), marking the initial recognition of this compound as a product of carbohydrates. The primary laboratory-scale synthesis of HMF from carbohydrates involves acid-catalyzed dehydration of hexose sugars, such as fructose or glucose. For fructose, the process proceeds through a series of enediol and carbonyl intermediates, ultimately eliminating three molecules of water to form HMF. The key reaction is represented as: \ceC6H12O6−>[H+][150−200°C]C6H6O3+3H2O\ce{C6H12O6 ->[H+][150-200°C] C6H6O3 + 3 H2O} where \ceC6H12O6\ce{C6H12O6} denotes fructose and \ceC6H6O3\ce{C6H6O3} is HMF, typically catalyzed by mineral acids like hydrochloric acid (HCl) or sulfuric acid (\ceH2SO4\ce{H2SO4}) in aqueous media. This dehydration is favored under batch conditions at elevated temperatures (150–200 °C), often in mixed solvents such as water/dimethyl sulfoxide (DMSO) to enhance solubility and suppress side reactions like rehydration to levulinic acid. For glucose, a less reactive precursor, synthesis requires an initial step to , which can be facilitated by bases, enzymes (e.g., glucose isomerase), or Lewis acids before the phase. Alternatively, glucose can dehydrate directly via the 3-deoxyglucosone (3-DG) intermediate, a key pathway involving retro-aldol cleavage and successive steps under Brønsted . Laboratory yields from reach up to 80% under optimized conditions, such as 0.1–1 M HCl in water/DMSO at 180 °C for 1–2 hours, while glucose yields are typically lower, ranging from 20–50%, due to the additional isomerization hurdle and competing . Alternative carbohydrate precursors include disaccharides like , which hydrolyzes to glucose and under acid conditions before , and such as (a ) that directly yields high HMF selectivity via selective and . can serve as a source through acid to glucose, followed by the aforementioned isomerization and , though this integrated process often results in moderate overall yields (around 40–60%) in laboratory settings. These routes highlight the versatility of feedstocks in fundamental HMF synthesis, with mechanistic insights derived from kinetic studies emphasizing the role of and solvent polarity in controlling selectivity.

Industrial production

Industrial production of hydroxymethylfurfural (HMF) primarily utilizes renewable feedstocks such as , including and wood, which undergo pretreatment and to yield C6 sugars like glucose and . Bio-based derived from serves as another key feedstock, leveraging established processes for scalability. These sources enable integration into models, minimizing reliance on petroleum-based inputs. Key industrial processes focus on one-pot conversions of these sugars using solid acid catalysts, such as zeolites and ion-exchange resins, to facilitate while mitigating side reactions. Biphasic systems, often combining water with (MIBK), extract HMF , improving separation and yields in continuous flow reactors. The first semi-commercial scale facility, operated by AVA Biochem in since 2014, employs a fully water-based process from biomass-derived sugars, with a capacity of 6 metric tons per year. Industrial yields typically range from 50% to 90%, though challenges include the formation of side products like and , as well as catalyst deactivation due to buildup. Post-2020 advances emphasize enzymatic cascades incorporating glucose isomerase for formation followed by dehydratases, offering milder conditions and reduced energy use compared to purely chemical routes, though still in pilot stages. Companies like Avantium are scaling up via the YXY , which intermediates through HMF ethers for downstream products, with a grant awarded in May 2025 to participate in a Michelin-led supporting large-scale HMF production in . Economic analyses indicate production costs of approximately $1,000–3,000 per ton, influenced by feedstock prices and efficiency, with potential reductions through integrated operations targeting below $1,500 per ton. Scalability remains promising for bio-based chemical markets, provided yields exceed 70% consistently.

Chemical reactions and derivatives

Oxidation and reduction reactions

Hydroxymethylfurfural (HMF) undergoes oxidation primarily at its and hydroxymethyl groups, leading to key products such as 2,5-furandicarboxylic acid (FDCA). The full oxidation to FDCA is achieved using the AMOCO process, which employs a homogeneous Co/Mn/Br system in acetic acid solvent under air or oxygen atmosphere, typically at temperatures of 130–170 °C. This process converts HMF to FDCA via sequential oxidation of the to and the alcohol to another , represented by the overall reaction: HMF+32O2→FDCA+H2O\text{HMF} + \frac{3}{2} \text{O}_2 \rightarrow \text{FDCA} + \text{H}_2\text{O} Optimized conditions in this system yield up to 95% FDCA from crude HMF feeds. Biocatalytic oxidation offers a greener alternative, utilizing enzymes like galactose oxidase (GOase) variants engineered for high activity toward HMF, often in aqueous media at ambient temperatures, achieving FDCA yields of 60–100% in multi-enzyme cascades. Partial oxidation of HMF targets specific functional groups under milder conditions. For instance, selective oxidation of the aldehyde group produces 5-hydroxymethyl-2-furoic (HMFCA), while further or alternative pathways yield 5-formyl-2-furoic (FFCA); these intermediates are accessed using TEMPO-mediated catalysis or catalysts like Pt/C at 50–100 °C in basic aqueous solutions, with yields exceeding 80% for HMFCA. Such controlled oxidations are valuable for isolating platform chemicals en route to FDCA. Reduction of HMF focuses on converting the aldehyde to a primary alcohol, yielding 2,5-bis(hydroxymethyl)furan (BHMF). This is commonly performed using gas with Ru-based catalysts, such as Ru/Co₃O₄, in alcoholic solvents like isopropanol at 150–190 °C and 10–30 bar H₂, achieving BHMF yields of 82–96%. (NaBH₄) serves as a milder in aqueous or methanolic media at , though catalytic is preferred for scalability. The reaction is: HMF+H2→BHMF\text{HMF} + \text{H}_2 \rightarrow \text{BHMF} These redox transformations typically occur in aqueous or alcoholic solvents at 50–150 °C, with optimized yields surpassing 90% for FDCA and 80% for BHMF. FDCA is a critical bio-based monomer for replacing in (PET), enabling sustainable polyesters like polyethylene furandicarboxylate (PEF) with improved barrier properties. BHMF, meanwhile, functions as a diol precursor for polyols in foams and polyesters.

Other reactions and key derivatives

HMF undergoes etherification reactions primarily at the , substituting the hydroxyl with alkyl or haloalkyl functionalities. A notable example is the conversion to 5-chloromethylfurfural (CMF) through treatment with , which proceeds under mild conditions and yields a stable, hydrophobic intermediate suitable for further transformations into fuels and chemicals. Etherification with alcohols, such as , forms 5-alkoxymethylfurfurals like 5-ethoxymethylfurfural (EMF), catalyzed by mesoporous solid acids (e.g., Al-MCM-41 or ZrO₂-SBA-15) with high selectivity (>90% for EMF) at moderate temperatures (60–100°C). Self-etherification, where the reacts intramolecularly or intermolecularly, can also occur over Sn-based catalysts to produce bis-methylene-linked furfurals. Esterification targets the hydroxymethyl moiety, forming esters that enhance HMF stability for downstream applications. Reaction with carboxylic acids or anhydrides, such as , yields HMF acetate or diacetate derivatives under acidic or basic , often achieving near-quantitative yields in solvent-free conditions. Acetalization of the group with alcohols (e.g., ) under produces cyclic acetals, providing protection against and enabling selective functionalization. These transformations are typically performed at to 80°C, with heterogeneous catalysts like resins improving recyclability and selectivity. Key derivatives of HMF arise from non-redox modifications, including ring-opening hydration to and . This reaction involves acid-catalyzed addition of water across the ring, followed by rearrangement and cleavage, achieving 95.6% selectivity to LA at 120°C in a biphasic system using a dual Brønsted-Lewis acid catalyst like HScCl₄. Another important derivative is 2,5-diformylfuran (DFF), obtained via selective oxidation of the hydroxymethyl and formyl groups, serving as a precursor for pharmaceuticals and resins. Under basic conditions, HMF undergoes self-condensation through mechanisms like the benzoin reaction, leading to oligomers that can polymerize into resins. This process, often initiated at pH 8–10 with or thiazolium catalysts, forms C–C bonds between groups, yielding furan-based polyols suitable for formulations when combined with phenolic compounds. A wide range of HMF derivatives, exceeding 50 reported structures, have been synthesized for niche applications, including amino alcohols via of the aldehyde with amines and reducing agents (e.g., NaBH₃CN), and dialdehydes like DFF for cross-linking agents.

Occurrence

In foods

Hydroxymethylfurfural (HMF) forms in foods primarily through two heat-induced pathways: the , involving the interaction of reducing sugars and leading to decomposition of intermediates like 3-deoxyglucosone, and , the direct thermal degradation of sugars without . These processes are most pronounced under acidic conditions at pH 3–5 and temperatures of 120–150 °C, where and cyclization of sugar fragments accelerate HMF production. HMF is prevalent in various processed foods, with concentrations varying by processing intensity. In honey, levels typically remain low in fresh samples but can reach up to 500 mg/kg in overheated or poorly stored products. , particularly instant varieties, often contains 100–3000 mg/kg due to , while baked goods like exhibit 10–100 mg/kg from . Fruit juices and dried fruits also show elevated HMF, sometimes exceeding 1 g/kg in concentrated or heat-treated forms. Several factors influence HMF accumulation in foods, including processing temperature and duration, which promote faster formation at higher levels; pH, with acidity enhancing reactivity; and sugar type, where generates the highest amounts compared to glucose or . Mitigation strategies include using lower heating temperatures, shorter processing times, or adding antioxidants to inhibit reactive intermediates. Since the 1970s, HMF has served as a key indicator of honey freshness and quality, with concentrations above 40 mg/kg signaling overheating or extended storage under suboptimal conditions. In the 2020s, the maintains regulatory limits of 40 mg/kg for general and 80 mg/kg for origins in tropical regions to ensure product integrity.

In natural and environmental sources

Hydroxymethylfurfural (HMF) is generated in natural environments through thermal processes involving degradation, particularly during wildfires and other burning events. In these scenarios, HMF forms as a product from carbohydrates in material, contributing to emissions alongside other furanic compounds. Laboratory simulations of burning have detected HMF in samples, though its reactivity leads to challenges in accurate quantification, suggesting potential underestimation in natural emissions. Low levels of HMF occur in certain beverages derived from natural , such as wine, where it arises from minor thermal or acidic conditions during the process. In unsweetened natural white wines, HMF concentrations are typically trace amounts, reaching a maximum of 2.5 mg/L, while dry wines may contain up to 3 mg/L without significant changes during . HMF is also present in tobacco and cigarette smoke, stemming from the pyrolytic decomposition of cellulose and added sugars during combustion. High concentrations of HMF have been reported in these sources, positioning smoke as a notable non-food environmental exposure route. In terms of environmental fate, HMF degrades primarily via photolysis and microbial processes, limiting its persistence in ecosystems. Photodegradation under UV irradiation follows pseudo-first-order kinetics, with rates influenced by initial concentration and leading to breakdown products like formic acid. Microbial degradation by bacteria and fungi, including species like Corynebacterium and Amycolatopsis, converts HMF to alcohols such as 5-hydroxymethylfurfuryl alcohol, often with high efficiency in aerobic and anaerobic conditions. Anaerobic studies indicate slow but complete biodegradation in wastewater-like systems, supporting its low environmental accumulation due to rapid transformation.

Applications

Industrial and material uses

Hydroxymethylfurfural (HMF) is recognized as a key platform chemical derived from , identified by the U.S. Department of Energy in its 2004 report as one of twelve promising building block chemicals that can be produced from sugars through biological or chemical conversions. This status underscores HMF's versatility as a renewable intermediate for value-added products, with ongoing recognition in assessments through the 2020s. In polymer applications, HMF serves as a precursor to 2,5-furandicarboxylic acid (FDCA) via oxidation, which is polymerized with bio-based to form polyethylene furanoate (PEF), a sustainable alternative to petroleum-derived (PET). PEF offers superior barrier properties for packaging, such as reduced oxygen permeability, making it suitable for bottles and films. Avantium, a leader in this technology, achieved commercialization milestones in 2024, including the startup of its FDCA flagship plant in the , enabling initial commercial production of PEF resins. HMF is hydrogenated to 2,5-dimethylfuran (DMF), a promising additive with an of 30 MJ/L, higher than (23 MJ/L) and comparable to , along with a high research number of 119 and immiscibility for blending stability. This positions DMF as a second-generation candidate to enhance engine performance and reduce emissions when mixed with conventional fuels. HMF-based furan resins are utilized in foundry applications, where derivatives like 2,5-bis(hydroxymethyl)furan (BHMF, produced via HMF reduction) form acid-cured binders for sand cores and molds in metal casting. These resins provide strong mechanical properties and thermal stability, enabling precise mold formation for automotive and machinery parts. Recent developments focus on sustainable furanic alternatives from HMF to reduce reliance on furfural-derived systems while maintaining performance in no-bake processes. Beyond these, HMF derivatives act as cross-linkers in coatings, enhancing and ; for instance, dihydroxymethylfurfural (DHMF) forms networks in bio-based formulations, improving resistance and mechanical strength. Advances from 2023 to 2025 include HMF-derived polyimines for recyclable thermosets in carbon fiber composites, allowing high-quality fiber recovery through , which supports circular manufacturing in and automotive sectors. Global HMF production reached approximately 4,800 metric tons in 2024, driven by demand in bio-based chemicals, with market projections indicating growth at a compound annual rate of about 3% to exceed 6,000 tons by 2030, fueled by expansions in polymer and fuel sectors.

Biomedical and pharmaceutical uses

Hydroxymethylfurfural (HMF) and its derivatives exhibit antioxidant properties by scavenging free radicals such as ABTS and DPPH in vitro, and inhibiting AAPH-induced hemolysis in a dose-dependent manner. These activities contribute to hepatoprotective effects against alcohol-induced oxidative liver injury, where HMF reduces reactive oxygen species (ROS) levels and enhances antioxidant enzyme expression in mouse models. In applications, HMF mitigates (LPS)-induced in RAW 264.7 macrophages by inhibiting MAPK, , and Akt/ signaling pathways, reducing proinflammatory production such as TNF-α and IL-6. This mechanism has been explored in models, where HMF derivatives alleviate intestinal and protect mucosal barriers in dextran sulfate sodium-induced in mice. HMF serves as a scaffold for pharmaceutical intermediates in synthesizing antibacterials, with derivatives like 2,5-furandicarboxylic acid (FCA) showing high binding affinity to LasR protein (-7 kcal/mol), indicating antimicrobial potential against bacterial . For , HMF-based prodrugs enable controlled release, such as in thiazolidine complexes that slowly liberate HMF to prolong survival and inhibit in (SCD) mouse models. formulations of HMF prodrugs further optimize for SCD treatment by enhancing oxygen affinity and reducing sickling under hypoxia. Recent research from 2015 to 2025 highlights HMF's neuroprotective potential, as it improves cognitive impairment in amyloid-β-induced mouse models by reducing and enhancing function. Computational studies further suggest HMF derivatives inhibit tau-related through binding to targets (-5.3 to -6.2 kcal/mol affinity). In anticancer applications, HMF modulates ROS to induce and G0/G1 arrest in A375 cells via mitochondrial pathways. As of 2025, no HMF-based drugs are approved for clinical use, though derivatives like Aes-103 have completed phase I trials for SCD, demonstrating safety, tolerability, and antisickling effects in healthy volunteers and patients. Preclinical hydrogel systems embedding HMF accelerate in rat models by promoting and deposition, but human trials remain pending.

Health and safety

Toxicity and biological effects

Hydroxymethylfurfural (HMF) exhibits low in animal models, with an oral LD50 greater than 2000 mg/kg in rats, indicating minimal risk from single high-dose exposures. Safety data further confirm an oral LD50 of approximately 2500 mg/kg in rats, with no significant behavioral effects beyond potential convulsions at extreme doses. However, HMF acts as an irritant to and eyes upon direct contact, causing mild to moderate in exposed tissues. Regarding genotoxicity, HMF itself shows no mutagenic activity in standard bacterial assays such as the Ames test without metabolic activation, but it can be bioactivated in mammalian systems to 5-sulfoxymethylfurfural (SMF), a metabolite that tests positive for mutagenicity at high concentrations. This bioactivation occurs via sulfotransferases, leading to SMF formation that reacts with DNA to produce adducts, particularly at the N7 position of guanine, through mechanisms resembling Maillard reaction pathways. In vitro studies, including the umu test and single-cell gel electrophoresis, demonstrate DNA damage induction by HMF or its metabolites in liver and bladder cells, though no clastogenic or aneugenic effects were observed in micronucleus assays. Chronic exposure to HMF has raised concerns about carcinogenic potential, with National Toxicology Program (NTP) studies providing some evidence of hepatocarcinogenicity in female B6C3F1 mice following long-term oral administration, based on increased incidences, though results were negative in rats and male mice. HMF has not been formally classified by the International Agency for Research on Cancer (IARC), placing it effectively in Group 3 (not classifiable as to its carcinogenicity to humans) due to inadequate human data and limited animal evidence. Animal studies also suggest possible links to gut inflammation, as HMF and related Maillard products may exacerbate inflammatory responses in the intestinal mucosa, potentially contributing to conditions like in . HMF is rapidly absorbed following oral and undergoes extensive in the liver, primarily via oxidation to 5-hydroxymethylfuroic acid (HMFA), 2,5-furandicarboxylic acid, and succinic acid semialdehyde, with ultimate conversion to or conjugation for excretion. In humans, approximately 60-80% of an administered dose is excreted in urine as metabolites within 48 hours, indicating efficient clearance and a on the order of hours. The primary exposure route for HMF is dietary, with average daily human intake estimated at 5-30 mg per person, primarily from thermally processed foods like , , and cereals, though levels vary widely based on consumption patterns. In industrial settings, may occur during production, posing risks to workers handling high concentrations. Infants represent a vulnerable group, as processed infant foods (e.g., fruit-based purees) can contain elevated HMF levels up to 144 mg/kg, while powdered milk formulas typically have lower levels (0.3-8 mg/kg), leading to relatively higher proportional intakes during early development.

Regulatory aspects

In the , hydroxymethylfurfural (HMF) is regulated as a indicator in under Council Directive 2001/110/EC, which establishes maximum limits of 40 mg/kg for general honey and 80 mg/kg for honey produced in tropical climates or blends containing tropical honey. These limits aim to ensure freshness and prevent excessive heat processing, with compliance verified through routine testing. In the United States, the (FDA) has not established specific regulatory limits for HMF in honey or most foods, though it is monitored as a process contaminant in formulas and other baby foods to assess damage and potential exposure risks. For industrial applications, the (OSHA) has not established a (PEL) for HMF, reflecting its classification as a non-regulated substance under current occupational standards. Under the EU's REACH regulation, HMF (CAS 67-47-0) is registered as a , requiring notification and safety data submission for manufacturers or importers handling quantities exceeding 1 tonne per year. Environmentally, HMF is listed on the Toxic Substances Control Act (TSCA) Inventory, subjecting it to reporting requirements for manufacturing, processing, or importation activities. In bio-refineries, wastewater discharge containing HMF is regulated under the National Pollutant Discharge Elimination System (NPDES), with permits often specifying limits for organic compounds like HMF below 1 mg/L to protect aquatic ecosystems, though exact thresholds vary by facility. Internationally, the Commission sets guidelines for HMF primarily in , recommending a maximum of 40 mg/kg as a process contaminant indicator to maintain quality in heated or stored products, with higher allowances up to 80 mg/kg for tropical origins. For other processed foods, HMF serves as a marker for products, but no universal numerical limits are prescribed beyond general contaminant principles. Recent assessments from 2020 to 2025 include the European Food Safety Authority's (EFSA) 2022 evaluation, which confirmed low health risks from HMF exposure in feed at typical dietary levels for bees.

Analysis

Detection methods

Detection of hydroxymethylfurfural (HMF) in samples typically begins with to isolate the compound from complex matrices such as foods, followed by qualitative methods for initial identification. Common extraction techniques include liquid-liquid extraction using , which effectively isolates HMF from and other food samples due to its solubility properties. For more intricate matrices like processed foods or , solid-phase extraction (SPE) is employed to remove interferences and concentrate HMF, often using cartridges with reversed-phase sorbents for cleanup prior to analysis. These preparatory steps ensure cleaner samples for subsequent detection, minimizing matrix effects that could obscure HMF signals. Colorimetric tests provide a simple, qualitative approach for detecting HMF based on its reaction with specific reagents to produce visible color changes indicative of furfural-like structures. In the Seliwanoff test, HMF reacts with under acidic conditions to form a -colored complex, allowing for preliminary identification in extracts. Similarly, the Winkler method involves HMF reacting with to yield a compound, which can be observed visually or measured spectrophotometrically for confirmation of presence. These tests are particularly useful for rapid screening in and sugary matrices, though they may cross-react with related aldehydes like . Chromatographic techniques facilitate the separation and initial screening of HMF from sample mixtures, enabling qualitative identification through retention behavior and detection. (TLC) serves as an early screening method, where HMF spots are visualized under UV light or with developing agents on silica plates, offering a low-cost option for confirming presence in extracts. (GC), often coupled with flame ionization or detection, separates HMF after derivatization to enhance volatility, suitable for volatile-rich food samples. (UV) detection at 280 nm is commonly integrated with these separations, exploiting HMF's characteristic absorption maximum for straightforward identification without additional reagents. Electrochemical methods leverage HMF's redox properties for sensitive, on-site detection, particularly in field applications. Sensors based on modified electrodes, such as nickel oxide nanoparticles on screen-printed carbon electrodes, detect HMF through voltammetric responses during oxidation, providing rapid qualitative signals in honey and food matrices. Portable paper-based electrochemical cells have also been developed, utilizing molecularly imprinted polymers to selectively bind HMF and generate measurable current changes for identification. These approaches are advantageous for their speed and minimal sample manipulation, though they require calibration for specificity. Quantitative accuracy of such detections is further refined in specialized techniques. Historical methods for HMF detection, emerging in the mid-20th century, laid the foundation for modern analyses, focusing on for honey evaluation. The Winkler method, introduced in 1955, employed derivatization followed by visible to detect HMF's colored product, becoming a standard for early quality assessments. By the late 1970s, the White method advanced this with UV difference using to eliminate interferences, improving reliability for post-1950s analyses. These pioneering techniques emphasized preparatory and color reactions, influencing subsequent chromatographic and electrochemical developments.

Quantification techniques

High-performance liquid chromatography with ultraviolet detection (HPLC-UV) serves as a widely adopted standard method for quantifying hydroxymethylfurfural (HMF) in matrices, employing a reverse-phase C18 column and a mobile phase composed of and , with a limit of detection (LOD) of approximately 0.1 mg/kg. This approach aligns with AOAC guidelines for and provides reliable quantification through calibration curves based on peak area integration at 280 nm. Typical conditions include isocratic at a flow rate of 1 mL/min, enabling separation from matrix interferents in samples like and . Liquid chromatography (LC-MS/MS) offers enhanced sensitivity for trace-level HMF quantification in biological fluids and complex foods, utilizing for improved accuracy and an below 0.01 mg/kg. Operating in multiple reaction monitoring mode with , this method employs C18 columns and acidic methanol-water gradients, achieving precise measurements down to 0.01 µg/kg in via deuterated internal standards. It is particularly valuable for low-concentration analyses where UV detection may lack specificity. Nuclear magnetic resonance (NMR) spectroscopy, specifically ¹H-NMR, enables direct quantification of HMF in pure samples or extracts through integration of characteristic proton signals at 9.5 ppm (aldehyde) and 4.6 ppm (hydroxymethyl), often following pH adjustment and addition of a reference standard like TSP. This technique provides structural confirmation alongside quantification, with recoveries ranging from 92% to 98% in honey, though it requires higher sample concentrations compared to chromatographic methods. Enzymatic assays, such as enzyme-linked immunosorbent assays () utilizing HMF-specific antibodies, facilitate high-throughput quantification in food products like , juices, and , with detection limits as low as 0.01 mg/kg and recoveries of 85–110%. These kits offer rapid colorimetric readout based on antigen-antibody binding, suitable for routine screening without advanced instrumentation. Recent HPLC methods reported in 2023 for HMF in processed foods like achieve LODs around 1.9 mg/kg with reliable validation. Common validation parameters across these methods include linearity over 0.1–1000 mg/kg, recoveries of 90–110%, and relative standard deviations below 10%, ensuring robustness for assessments. Sample preparation for these techniques generally involves simple dilution and to minimize matrix effects.

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