Hydroxymethylfurfural

HMF was first reported in 1875 as an intermediate in the formation of levulinic acid from sugar and sulfuric acid.{{cite journal |last1=Grote |first1=A. Freiherrn V. |last2=Tollens |first2=B. |title=Untersuchungen über Kohlenhydrate. I. Ueber die bei Einwirkung von Schwefelsäure auf Zucker entstehende Säure (Levulinsäure) |journal=Justus Liebig's Annalen der Chemie |volume=175 |issue=1–2 |year=1875 |pages=181–204 |issn=0075-4617 |doi=10.1002/jlac.18751750113 |url=https://zenodo.org/record/1427341}} This remains the classical route, with 6-carbon sugars (hexoses) such as fructose undergoing acid catalyzed poly-dehydration.{{cite journal |title=Phase Modifiers Promote Efficient Production of Hydroxymethylfurfural from Fructose |author1=Yuriy Román-Leshkov |author2=Juben N. Chheda |author3=James A. Dumesic |journal=Science |year=2006 |volume=312 |issue=5782 |pages=1933–1937 |doi=10.1126/science.1126337 |pmid=16809536 |bibcode=2006Sci...312.1933R |s2cid=38432592}}{{cite journal |doi=10.15227/orgsyn.093.0029 |volume=93 |title=Synthesis of 5-(Hydroxymethyl)furfural (HMF) |year=2016 |journal=Organic Syntheses |pages=29–36 |last1=Simeonov |first1=Svilen |doi-access=free}} 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.

File:NewhydroxymethylfurfuralSynthesis.png (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. 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,{{cite journal |last1=Brownlee |first1=Harold J. |last2=Miner |first2=Carl S. |title=Industrial Development of Furfural |journal=Industrial & Engineering Chemistry |volume=40 |issue=2 |year=1948 |pages=201–204 |issn=0019-7866 |doi=10.1021/ie50458a005}} 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,{{cite journal |last1=Zakrzewska |first1=Małgorzata E. |last2=Bogel-Łukasik |first2=Ewa |last3=Bogel-Łukasik |first3=Rafał |title=Ionic Liquid-Mediated Formation of 5-Hydroxymethylfurfural—A Promising Biomass-Derived Building Block |journal=Chemical Reviews |volume=111 |issue=2 |year=2011 |pages=397–417 |issn=0009-2665 |doi=10.1021/cr100171a |pmid=20973468}}{{cite journal |last1=Eminov |first1=Sanan |last2=Wilton-Ely |first2=James D. E. T. |last3=Hallett |first3=Jason P. |title=Highly Selective and Near-Quantitative Conversion of Fructose to 5-Hydroxymethylfurfural Using Mildly Acidic Ionic Liquids |journal=ACS Sustainable Chemistry & Engineering |date=2 March 2014 |volume=2 |issue=4 |pages=978–981 |doi=10.1021/sc400553q |doi-access=free |hdl=10044/1/31478 |hdl-access=free}} 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.{{cite journal |last1=Teong |first1=Siew Ping |last2=Yi |first2=Guangshun |last3=Zhang |first3=Yugen |title=Hydroxymethylfurfural production from bioresources: past, present and future |journal=Green Chemistry |volume=16 |issue=4 |year=2014 |pages=2015 |issn=1463-9262 |doi=10.1039/c3gc42018c}}

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, which has been proposed as a replacement for terephthalic acid in the production of polyesters.{{cite journal |last1=Sousa |first1=Andreia F. |last2=Vilela |first2=Carla |last3=Fonseca |first3=Ana C. |last4=Matos |first4=Marina |last5=Freire |first5=Carmen S. R. |last6=Gruter |first6=Gert-Jan M. |last7=Coelho |first7=Jorge F. J. |last8=Silvestre |first8=Armando J. D. |title=Biobased polyesters and other polymers from 2,5-furandicarboxylic acid: a tribute to furan excellency |journal=Polym. Chem. |volume=6 |issue=33 |year=2015 |pages=5961–5983 |issn=1759-9954 |doi=10.1039/C5PY00686D}}{{cite journal |last1=Zhang |first1=Daihui |last2=Dumont |first2=Marie-Josée |title=Advances in polymer precursors and bio-based polymers synthesized from 5-hydroxymethylfurfural |journal=Journal of Polymer Science Part A: Polymer Chemistry |date=1 May 2017 |volume=55 |issue=9 |pages=1478–1492 |doi=10.1002/pola.28527 |bibcode=2017JPoSA..55.1478Z |doi-access=free |hdl=20.500.11794/100964 |hdl-access=free}} 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.

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.{{cite journal |pmid=20005914 |last1=Arribas-Lorenzo |year=2010 |first1=G |pages=644–9 |issue=2 |volume=48 |last2=Morales |first2=FJ |title=Estimation of dietary intake of 5-hydroxymethylfurfural and related substances from coffee to Spanish population |journal=Food and Chemical Toxicology |doi=10.1016/j.fct.2009.11.046 |hdl=10261/82147}} 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.{{cite journal |title=A novel UHPLC method for determining the degree of coffee roasting by analysis of furans |journal=Food Chemistry |volume=341 |pages=128165 |doi=10.1016/j.foodchem.2020.128165 |issn=0308-8146 |year=2021 |last1=Macheiner |first1=Lukas |last2=Schmidt |first2=Anatol |last3=Karpf |first3=Franz |last4=Mayer |first4=Helmut K. |issue=Pt 1 |pmid=33038777}}

It is a good wine storage time−temperature marker,{{cite journal |last1=Serra-Cayuela |first1=A. |last2=Jourdes |first2=M. |last3=Riu-Aumatell |first3=M. |last4=Buxaderas |first4=S. |last5=Teissedre |first5=P.-L. |last6=López-Tamames |first6=E. |year=2014 |title=Kinetics of Browning, Phenolics, and 5-Hydroxymethylfurfural in Commercial Sparkling Wines |journal=J. Agric. Food Chem. |volume=62 |issue=5 |pages=1159–1166 |doi=10.1021/jf403281y |pmid=24444020}} especially in sweet wines such as Madeira{{cite journal |doi=10.1016/j.foodres.2010.11.011 |volume=44 |title=Evolution of 5-hydroxymethylfurfural (HMF) and furfural (F) in fortified wines submitted to overheating conditions |year=2011 |journal=Food Research International |pages=71–76 |last1=Pereira |first1=V. |hdl=10400.14/7635 |hdl-access=free}} and those sweetened with grape concentrate arrope.{{cite journal |doi=10.1111/j.1365-2621.1948.tb16621.x |volume=13 |year=1948 |journal=Journal of Food Science |pages=264–269 |last1=Amerine |first1=Maynard A. |title=Hydroxymethylfurfural in California Wines |issue=3 |pmid=18870652}}

File:Dictyophora indusiata Feb 2010.JPG. 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,{{cite journal |last1=Ruiz-Matute |first1=AI |last2=Weiss |first2=M |last3=Sammataro |first3=D |last4=Finely |first4=J |last5=Sanz |first5=ML |title=Carbohydrate composition of high-fructose corn syrups (HFCS) used for bee feeding: effect on honey composition |journal=Journal of Agricultural and Food Chemistry |volume=58 |issue=12 |pages=7317–22 |year=2010 |pmid=20491475 |doi=10.1021/jf100758x}} 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.{{cite journal |pmc=5884753 |pmid=29619623 |doi=10.1186/s13065-018-0408-3 |volume=12 |title=5-Hydroxymethylfurfural (HMF) levels in honey and other food products: effects on bees and human health |year=2018 |journal=Chem Cent J |page=35 |last1=Shapla |first1=UM |last2=Solayman |first2=M |last3=Alam |first3=N |last4=Khalil |first4=MI |last5=Gan |first5=SH |issue=1 |doi-access=free}}

Higher quantities of HMF are found naturally in coffee and dried fruit. Several types of roasted coffee contained between 300 – 2900 mg/kg HMF.{{cite journal |last1=Murkovic |first1=M |last2=Pichler |first2=N |title=Analysis of 5-hydroxymethylfurfual in coffee, dried fruits and urine |journal=Molecular Nutrition & Food Research |volume=50 |issue=9 |pages=842–6 |year=2006 |pmid=16917810 |doi=10.1002/mnfr.200500262}} Dried plums were found to contain up to 2200 mg/kg HMF. In dark beer 13.3 mg/kg were found,{{cite journal |last1=Husøy |first1=T |last2=Haugen |first2=M |last3=Murkovic |first3=M |last4=Jöbstl |first4=D |last5=Stølen |first5=LH |last6=Bjellaas |first6=T |last7=Rønningborg |first7=C |last8=Glatt |first8=H |last9=Alexander |first9=J |title=Dietary exposure to 5-hydroxymethylfurfural from Norwegian food and correlations with urine metabolites of short-term exposure |journal=Food and Chemical Toxicology |volume=46 |issue=12 |pages=3697–702 |year=2008 |pmid=18929614 |doi=10.1016/j.fct.2008.09.048}} bakery-products contained between 4.1 – 151 mg/kg HMF.{{cite journal |last1=Ramírez-Jiménez |first1=A |title=Hydroxymethylfurfural and methylfurfural content of selected bakery products |journal=Food Research International |volume=33 |page=833 |year=2000 |doi=10.1016/S0963-9969(00)00102-2 |issue=10 |last2=Garcı́a-Villanova |first2=Belén |last3=Guerra-Hernández |first3=Eduardo}}

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. 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.

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.{{cite journal |last1=Abraham |first1=Klaus |last2=Gürtler |first2=Rainer |last3=Berg |first3=Katharina |last4=Heinemeyer |first4=Gerhard |last5=Lampen |first5=Alfonso |last6=Appel |first6=Klaus E. |title=Toxicology and risk assessment of 5-Hydroxymethylfurfural in food |date=May 2011 |journal=Molecular Nutrition & Food Research |volume=55 |issue=5 |pages=667–678 |doi=10.1002/mnfr.201000564 |issn=1613-4133 |pmid=21462333}}

{{Clear}}

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.{{cite journal |last1=Abdulmalik |first1=O |last2=Safo |first2=MK |last3=Chen |first3=Q |last4=Yang |first4=J |last5=Brugnara |first5=C |last6=Ohene-Frempong |first6=K |last7=Abraham |first7=DJ |last8=Asakura |first8=T |title=5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells |journal=British Journal of Haematology |volume=128 |issue=4 |pages=552–61 |year=2005 |pmid=15686467 |doi=10.1111/j.1365-2141.2004.05332.x |s2cid=22342114 |doi-access=free}} Under the development code Aes-103, HMF has been considered for the treatment of sickle cell disease.{{cite web |title=Aes-103 for Sickle Cell Disease |date=2015-03-18 |url=https://ncats.nih.gov/trnd/projects/complete/aes-103-sickle-cell |access-date=2022-01-20 |website=National Center for Advancing Translational Sciences |language=en}}

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.{{cite journal |last1=White Jr. |first1=J. W. |title=Spectrophotometric method for hydroxymethylfurfural in honey |journal=Journal of the Association of Official Analytical Chemists |date=1979 |volume=62 |issue=3 |pages=509–514 |doi=10.1093/jaoac/62.3.509 |pmid=479072 |doi-access=free}} 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).{{cite journal |last1=Schultheiss |first1=J. |last2=Jensen |first2=D. |last3=Galensa |first3=R. |doi=10.1016/S0021-9673(99)01086-9 |pmid=10890522 |title=Determination of aldehydes in food by high-performance liquid chromatography with biosensor coupling and micromembrane suppressors |year=2000 |volume=880 |issue=1–2 |pages=233–42 |journal=Journal of Chromatography A}}{{cite journal |last1=Gaspar |first1=Elvira M.S.M. |last2=Lucena |first2=Ana F.F. |title=Improved HPLC methodology for food control – furfurals and patulin as markers of quality |doi=10.1016/j.foodchem.2008.11.097 |year=2009 |page=1576 |volume=114 |journal=Food Chemistry |issue=4}}

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.{{cite journal |last1=Kang |first1=Eun-Sil |last2=Hong |first2=Yeon-Woo |last3=Chae |first3=Da Won |last4=Kim |first4=Bora |last5=Kim |first5=Baekjin |last6=Kim |first6=Yong Jin |last7=Cho |first7=Jin Ku |last8=Kim |first8=Young Gyu |title=From Lignocellulosic Biomass to Furans via 5-Acetoxymethylfurfural as an Alternative to 5-Hydroxymethylfurfural |journal=ChemSusChem |date=13 April 2015 |volume=8 |issue=7 |pages=1179–1188 |doi=10.1002/cssc.201403252 |pmid=25619448 |issn=1864-564X}}

{{Reflist|30em}}

Category:Furfurals

Category:Hydroxymethyl compounds