Hydroxymethylfurfural (HMF), also 5-(hydroxymethyl)furfural, is an
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
formed by the
dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
of reducing sugars. 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
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as furans.
Furan is a colorless, flammable, highly ...
ring, containing both
aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
and
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
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. HMF is classified as a food improvement agent and is primarily being used in the food industry in form of a
food additive
Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives have been used for centuries as part of an effort to preserve food, for example vinegar (pickling), salt (salt ...
as a biomarker as well as a flavoring agent for food products. It is also produced industrially on a modest scale as a
carbon-neutral
Carbon neutrality is a state of net-zero carbon dioxide emissions. This can be achieved by balancing emissions of carbon dioxide with its removal (often through carbon offsetting) or by eliminating emissions from society (the transition to the "p ...
feedstock for the production of fuels and other chemicals.
Production and reactions
HMF was first reported in 1875 as an intermediate in the formation of
levulinic acid
Levulinic acid, or 4-oxopentanoic acid, is an organic compound with the formula CH3C(O)CH2CH2CO2H. It is classified as a keto acid. This white crystalline solid is soluble in water and polar organic solvents. It is derived from degradation of cel ...
from sugar and sulfuric acid. This remains the classical route, with 6-carbon
sugars
Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...
(
hexoses
In chemistry, a hexose is a monosaccharide (simple sugar) with six carbon atoms. The chemical formula for all hexoses is C6H12O6, and their molecular weight is 180.156 g/mol.
Hexoses exist in two forms, open-chain or cyclic, that easily conver ...
) such as
fructose
Fructose, or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galacto ...
undergoing acid catalyzed poly-dehydration. When
hydrochloric acid
Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid
Acid strength is the tendency of an acid, symbol ...
is used 5-chloromethylfurfural is produced instead of HMF. Similar chemistry is seen with 5-carbon sugars (
pentoses
In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atoms. The chemical formula of many pentoses is , and their molecular weight is 150.13 g/mol.furfural.
The classical approach tends to suffer from poor yields as HMF continues to react in aqueous acid, forming
levulinic acid
Levulinic acid, or 4-oxopentanoic acid, is an organic compound with the formula CH3C(O)CH2CH2CO2H. It is classified as a keto acid. This white crystalline solid is soluble in water and polar organic solvents. It is derived from degradation of cel ...
. 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, HMF was not produced on a commercial scale until over 90 years later. The first production plant coming online in 2013. Numerous synthetic technologies have been developed, including the use of
ionic liquids
An ionic liquid (IL) is a salt in the liquid state. In some contexts, the term has been restricted to salts whose melting point is below a specific temperature, such as . While ordinary liquids such as water and gasoline are predominantly made of ...
reactive distillation
Reactive may refer to:
*Generally, capable of having a reaction (disambiguation)
*An adjective abbreviation denoting a bowling ball coverstock made of reactive resin
*Reactivity (chemistry)
*Reactive mind
*Reactive programming
See also
*Reactanc ...
and solid acid catalysts to either remove the HMF before it reacts further or to otherwise promote its formation and inhibit its decomposition.
Derivatives
HMF itself has few applications. It can however be converted into other more useful compounds. Of these the most important is
2,5-furandicarboxylic acid
2,5-Furandicarboxylic acid (FDCA) is an organic chemical compound consisting of two carboxylic acid groups attached to a central furan ring. It was first reported as ''dehydromucic acid'' by Rudolph Fittig and Heinzelmann in 1876, who produced it v ...
, which has been proposed as a replacement for terephthalic acid in the production of
polyesters
Polyester is a category of polymers that contain the ester functional group in every repeat unit of their main chain. As a specific material, it most commonly refers to a type called polyethylene terephthalate (PET). Polyesters include natural ...
. HMF can be converted to 2,5-dimethylfuran (DMF), a liquid that is a potential biofuel with a greater energy content than
bioethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
.
Hydrogenation
Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a Catalysis, catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or S ...
of HMF gives 2,5-bis(hydroxymethyl)furan. Acid-catalysed hydrolysis converts HMF into gamma-hydroxyvaleric acid and
gamma-valerolactone
γ-Valerolactone (GVL) is an organic compound with the formula C5H8O2. This colourless liquid is one of the more common lactones. GVL is chiral but is usually used as the racemate. It is readily obtained from cellulosic biomass and is a potenti ...
, with loss of formic acid.
Occurrence in food
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
The Maillard reaction ( ; ) is a chemical reaction between amino acids and reducing sugars that gives browned food its distinctive flavor. Seared steaks, fried dumplings, cookies and other kinds of biscuits, breads, toasted marshmallows, and man ...
as well as during
caramelization
Caramelization is a process of browning of sugar used extensively in cooking for the resulting sweet nutty flavor and brown color. The brown colors are produced by three groups of polymers: caramelans (C24H36O18), caramelens (C36H50O25), and c ...
. In these foods it is also slowly generated during storage. Acid conditions favour generation of HMF. 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). It is also formed during coffee roasting, with up to 769 mg/kg.
It is a good
wine storage
Wine is an alcoholic drink typically made from fermented grapes. Yeast consumes the sugar in the grapes and converts it to ethanol and carbon dioxide, releasing heat in the process. Different varieties of grapes and strains of yeasts are m ...
time−temperature marker, especially in
sweet wine
Dessert wines, sometimes called pudding wines in the United Kingdom, are sweet wines typically served with dessert.
There is no simple definition of a dessert wine. In the UK, a dessert wine is considered to be any sweet wine drunk with a meal ...
s such as
Madeira
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, song_type = Regional anthem
, image_map=EU-Portugal_with_Madeira_circled.svg
, map_alt=Location of Madeira
, map_caption=Location of Madeira
, subdivision_type=Sovereign st ...
and those sweetened with grape concentrate
arrope
Grape syrup is a condiment made with concentrated grape juice. It is thick and sweet because of its high ratio of sugar to water. Grape syrup is made by boiling grapes, removing their skins, squeezing them through a sieve to extract the juice, a ...
.
HMF can be found in low amounts in
honey
Honey is a sweet and viscous substance made by several bees, the best-known of which are honey bees. Honey is made and stored to nourish bee colonies. Bees produce honey by gathering and then refining the sugary secretions of plants (primar ...
, fruit-
juice
Juice is a drink made from the extraction or Cold-pressed juice, pressing of the natural liquid contained in fruit and vegetables. It can also refer to liquids that are flavored with concentrate or other biological food sources, such as meat ...
s and
UHT
Ultra-high temperature processing (UHT), ultra-heat treatment, or ultra-pasteurization is a food processing technology that sterilizes liquid food by heating it above – the temperature required to kill bacterial endospores – for 2 ...
-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, 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.
Higher quantities of HMF are found naturally in coffee and dried fruit. Several types of roasted coffee contained between 300 – 2900 mg/kg HMF. Dried plums were found to contain up to 2200 mg/kg HMF. In dark beer 13.3 mg/kg were found, bakery-products contained between 4.1 – 151 mg/kg HMF.
It can be found in
glucose syrup
Glucose syrup, also known as confectioner's glucose, is a syrup made from the hydrolysis of starch. Glucose is a sugar. Maize (corn) is commonly used as the source of the starch in the US, in which case the syrup is called " corn syrup", but glu ...
.
HMF can form in
high-fructose corn syrup
High-fructose corn syrup (HFCS), also known as glucose–fructose, isoglucose and glucose–fructose syrup, is a sweetener made from corn starch. As in the production of conventional corn syrup, the starch is broken down into glucose by enzy ...
(HFCS), levels around 20 mg/kg HMF were found, increasing during storage or heating. This is a problem for American
beekeepers
A beekeeper is a person who keeps honey bees.
Beekeepers are also called honey farmers, apiarists, or less commonly, apiculturists (both from the Latin '' apis'', bee; cf. apiary). The term beekeeper refers to a person who keeps honey bees i ...
because they use HFCS as a source of sugar when there are not enough
nectar
Nectar is a sugar-rich liquid produced by plants in glands called nectaries or nectarines, either within the flowers with which it attracts pollinating animals, or by extrafloral nectaries, which provide a nutrient source to animal mutualists ...
sources to feed
honeybees
A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current cosmo ...
, and HMF is toxic to them. Adding bases such as soda ash or potash to neutralize the HFCS slows the formation of HMF.
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.
Biomedical
A major
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
in humans is 5-hydroxymethyl-2-furoic acid (HMFA), which is excreted in urine.
HMF bind intracellular sickle hemoglobin (HbS). Preliminary ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' studies using transgenic sickle mice showed that orally administered 5HMF inhibits the formation of sickled cells in the blood. Under the development code Aes-103, HMF has been considered for the treatment of
sickle cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
.
Quantification
Today,
HPLC
High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
with UV-detection is the reference-method (e.g. DIN 10751-3). Classic methods for the quantification of HMF in food use
photometry Photometry can refer to:
* Photometry (optics), the science of measurement of visible light in terms of its perceived brightness to human vision
* Photometry (astronomy), the measurement of the flux or intensity of an astronomical object's electro ...
. The method according to White is a differential UV-photometry with and without sodium bisulfite-reduction of HMF. Winkler photometric method is a colour-reaction using p-
toluidine
There are three isomers of toluidine, which are organic compounds. These isomers are ''o''-toluidine, ''m''-toluidine, and ''p''-toluidine, with the prefixed letter abbreviating, respectively, ''ortho''; ''meta''; and ''para''. All three are aryl ...
and
barbituric acid
Barbituric acid or malonylurea or 6-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in water. Barbituric acid is the parent compound of barbiturate drugs, although barbituric acid i ...
( 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).
Other
HMF is an intermediate in the titration of hexoses in the
Molisch's test
Molisch's test is a sensitive chemical test, named after Austrian botanist Hans Molisch, for the presence of carbohydrates, based on the dehydration of the carbohydrate by sulfuric acid or hydrochloric acid to produce an aldehyde, which condenses ...
. In the related
Bial's test
Bial's test is a chemical test for the presence of pentoses. It is named after Manfred Bial, a German physician. The components include orcinol, hydrochloric acid, and ferric chloride. A pentose, if present, will be dehydrated to form furfural ...
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.
AMF, acetoxymethyl furfural, is also bio-derived green platform chemicals as an alternative to HMF.