Synthesis, chemistry and applications of 5-hydroxymethylfurfural and its derivatives

The prospect of exciting research activity in the chemistry of furfural derived compounds such as 
5-hydroxymethylfurfural (HMF), 2,5-furandicarbaldehyde and 2,5-furan-dicarboxylic acid 
prompted the writing of this article. As the field of application of these compounds is really 
enormous, it is no wonder that research in this area, starting at the end of 19th century, is still 
being developed. Numerous important scientific groups are carrying out studies on the synthesis, 
and applications of HMF and its derivatives. Notable among these are, Gaset (Toulouse), 
Descotes (Lyon), Lichtenthaler (Darmstadt), and Gelas (Clermont-Ferrand). Not only academic 
scientists are interested in this subject, the chemical industry, is represented by sugar companies 
such as Beghin-Say, and Suddeutsche Zucker. Despite this interest, there are not many 
comprehensive monographs or reviews covering the chemistry of HMF. Two classic reviews, by 
Newth and by Feather and Harris, appeared in 1951 and 1973 respectively. Reviews by Gaset 
et al.,3 Faury et al. and by Kuster are more recent, but they are not detailed. An important 
review review by Cottier and Descotes6 appeared in 1991. 
This review is written to update those above, to summarize the contributions of the last 100 
years; and to emphasize recent developments especially in electrochemistry, and on dialdehyde 
and diacid chemistry.


Introduction
The prospect of exciting research activity in the chemistry of furfural derived compounds such as 5-hydroxymethylfurfural (HMF), 2,5-furandicarbaldehyde and 2,5-furan-dicarboxylic acid prompted the writing of this article.As the field of application of these compounds is really enormous, it is no wonder that research in this area, starting at the end of 19 th century, is still being developed.Numerous important scientific groups are carrying out studies on the synthesis, and applications of HMF and its derivatives.Notable among these are, Gaset (Toulouse), Descotes (Lyon), Lichtenthaler (Darmstadt), and Gelas (Clermont-Ferrand).Not only academic scientists are interested in this subject, the chemical industry, is represented by sugar companies such as Beghin-Say, and Süddeutsche Zucker.Despite this interest, there are not many comprehensive monographs or reviews covering the chemistry of HMF.Two classic reviews, by Newth 1 and by Feather and Harris, 2 appeared in 1951 and 1973 respectively.Reviews by Gaset et al., 3 Faury et al. 4 and by Kuster 5 are more recent, but they are not detailed.An important review review by Cottier and Descotes 6 appeared in 1991.
This review is written to update those above, to summarize the contributions of the last 100 years; and to emphasize recent developments especially in electrochemistry, and on dialdehyde and diacid chemistry.

PART A. 5-HYDROXYMETHYLFURFURAL (HMF) 1. A historical outline of studies on 5-hydroxymethylfurfural (HMF)
5-Hydroxymethylfurfural (HMF) 1 has been of interest since the last decade of the 19 th century.In 1895 Düll 7 and Kiermeyer 8 working independently, published a method of synthesis and chemical reactions of the compound, which they called "oxymethylfurfurol".
Later on, British chemists started their conquest; Fenton, 9 Gostling 10 and Robinson 11 published the results of their studies on HMF.In 1919, Middendorp 12 presented the full and the detailed study concerning the synthesis, the physical characterisation and the chemical behaviour of HMF.
Several years later other authors published their results, as for example Reichstein 13,14 and Haworth and Jones 15 -especially the latter brought immense progress in the chemistry of HMF.They worked out the modern method of its synthesis and studied the mechanism of its formation.From among a great number of papers concerning the chemistry of HMF, Karashima's article is worth mentioning. 16He worked out the method of synthesis of 5-acetoxymethylfurfural directly from HMF and fully characterised this compound.He reported also the formation of 5hydroxymethylfurfurylideneacetic acid by the Perkin condensation of HMF with acetic anhydride.
Till now, over 1000 papers have been published, which is a proof for the great importance of this kind of compounds.It is not possible in this work to quote all of these articles, but some reviews are worth mentioning.In the "Advances in Carbohydrate Chemistry" series, two articles were published, first by Newth 1 in 1951, the second appeared 20 years later by Feather. 2 Moye 17 has written a review describing methods of the preparation and industrial applications of HMF. to the enol 2. .• When the reaction was carried out in D 2 O starting from fructose, deuterium was absent in HMF.If 3-deoxyglycosulose 3 formed in the course of the reaction, one should expect a carbondeuterium bond due to the keto-enol tautomerism 2 .

Scheme 2 2.2. The kinetics of the HMF synthesis
All described methods of the synthesis of HMF require the utilisation of the thermal dehydration of hexoses in acidic medium.These conditions cause some difficulties in isolation of HMF, especially as HMF is a very active and unstable compound.Kuster 5 established factors determining the rate of the formation of HMF: •The sort of the substrate and the hydrolysis degree •The kind and the concentration of a catalyst •The time and the temperature of the reaction •The concentration of a polymer and the rate of the polymerisation •The type of solvent and the stability of HMF in given conditions The synthesis is more efficient and more selective when started from ketohexoses than from aldohexoses.For example, the hydrolysis of sucrose in an aqueous medium is much faster than the dehydration and a glucose part is always present in a post-reaction mixture.It is to state that due to a greater stability of the structure of glucose, it enolyses in a very low degree and the enolisation is a determining factor of the HMF formation from glucose (Scheme 2).Moreover, glucose can condense to form oligosaccharides bearing reducing groups, which may react with intermediates or with HMF itself.This would result in a cross-polymerisation. Despite, glucose is still utilised in industry for the preparation of HMF because of its price lower than fructose 6 .
The dehydration of hexoses is catalysed by protonic acids as well as by Lewis acids.First syntheses of HMF were catalysed by oxalic acid 7,8,12,15 and till now nearly one hundred inorganic and organic compounds were positively qualified as catalysts for the HMF synthesis.Cottier 6 divided catalysts into five groups; they are collected in Table 1.
Iodine catalysis allowed performing the dehydration even from aldohexoses.Bonner et al. 24,25 using this method, converted sucrose into HMF in 20% yield.Morikawa 26 utilised iodine as a catalyst to obtain HMF in 64% yield.The use of organic and inorganic salts in the synthesis of HMF was the subject of numerous works.Mednic 27,28 proposed to utilise ammonium phosphates (the yield 23%), triethylamine phosphate (36%) or pyridinium phosphate.The latter allowed obtaining HMF in 44% yield.Nakamura 29 invented the catalysis with zirconium phosphate and zirconyl chloride, a further development of this method 30 allowed improving the yield up to 90%.
Smith 32 as well as Garber and Jones 33 proposed utilising ammonium sulphate; Hales et al. 34 as well as scientists from Atlas Powder Lab. 35applied chromium trichloride or zinc chloride.Works concerning the application of ion-exchange resins for the synthesis of HMF are the most numerous.Nakamura 36 investigated the influence of a strongly acidic ion exchange resin and obtained HMF in 80% yield.Gaset et al. 37,38 utilised Levatit® SPC-108, to form HMF in 70-80% yield.Researchers from Noguchi Institute 39 patented the use of ion-exchange resins such as Amberlite® IR-116 or Diaion® PK-228 cross-linked with divinylbenzene.Some authors 40,41 claimed Diaion® PK-216 to be the most efficient.In both cases HMF was obtained in 90% yield.
Apart from the methods described above, it is worth to mention works by Mercadier, 42 Rigal, 43 El-Hajj 44 or Rapp. 20Their syntheses were also based on ion exchange and gave HMF in high yields.
The type of solvent and its influence on the efficiency of the dehydration is closely connected with temperature conditions.Cottier 6 divided methods into 5 groups depending on the type of solvent and the temperature of the process: •Aqueous processes carried out at temperatures below 200 The methods belonging to the first group are very convenient in the ecological point of view, but unfortunately they are not very efficient.Studies performed by laboratories of Suddeutsche Zucker showed that the maximum yield of HMF obtained via Rapp's procedure 20 is about 30%.Cottier 45 reported that the application of ion-exchange resins in an aqueous medium allowed formation of HMF in satisfactory yield.Depending on the mode of the isolation, he obtained it in 28% or 26% yield.They observed no influence of high dilution on the efficiency.
The second group of methods is based on pyrolitic processes.It was noted that the yield was increased in these reactions up to 58% and that the time of the reaction was shortened.Soluble polymeric products were detected instead of insoluble humic acids.Non-aqueous solvents require high dilution system; owing to the hydrophilic character of reagents.Various solvents were tested: Bonner 24,25 and Shur et al. 46 carried out the reaction in DMF, Brown 47 -in acetonitrile.Morikawa 26 proposed the application of quinoline and Smythe and Moye 48,49 performed the reaction in polyglycol ethers.The greatest number of papers described the utilisation of DMSO as a solvent in the HMF synthesis.Nakamura, 29,30,36 Noguchi Institute 39 and Gaset et al. 37,38 carried out reactions catalysed by ion exchange resins in DMSO.Mussau 50 performed the reaction without a catalyst, carrying it out in DMSO, too.Problems concerning the solubility of hexoses in organic solvents were resolved by the application of mixed-solvent (water-organic) systems.Chemists worked on these methods for a long time, Teunissen 51 , in 1931 proposed to use homogeneous systems for the synthesis of HMF.Now numerous papers describing various mixed systems have appeared.Peniston 52 utilised n-butanol, Mednic 27,28 and Hales 34 dioxane.Atlas Powder Co Laboratories 35 and Kuster [53][54][55][56] tested polyethylene glycols.The last method allowed a decrease in the degree of HMF degradation to levulinic acid.
Reactions run without a solvent resulted in diminished formation of levulinic acid and humic acids.Fayet and Gelas 31 worked with equimolar amounts of hexoses and pyridinium salts to obtain HMF in 70% yield.Neyret 57 tested the use of lower amounts of pyridinium salts other than those used by Fayet and Gelas.The best results were obtained with pyridinium oxalate, although the yield did not exceed 20 %, the ecological value of this method allowed using it in an industrial scale.Cottier 45 worked out a nice, clean and efficient laboratory method of preparation of HMF.According to his description the irradiation with microwaves of aqueous fructose (or sucrose) mixed with inorganic phosphates for 3 minutes gave HMF in 28%.
Chemists continue studies on HMF synthesis.Ponder and Richards 58 tested the chemical behaviour of D-glucose in the vacuum pyrolysis conditions, in the presence of such salts as sodium chloride, calcium acetate, and bases such as sodium or calcium hydroxide.The reaction lasted 30 minutes and it led to several anhydro-fructofuranoses and to HMF.Nakama et al. 59 studied the reaction of various disaccharides and monosaccharides such as: O 4 -β-Dgalactopyranosyl-D-glucose, O 4 -β-D-glucopyranosyl-D-glucose, D-mannose, D-glucose and Dgalactose with phenylalanine.All reactions were carried out in water, at 98 °C and lasted 10 hours leading to 5-hydroxymethylfurfural in fair yield.Salomon and co-workers 60 tested catalytic properties of tributylstannoxane in the hydrolysis of 5-acetoxymethylfurfural.The reaction was carried out in benzene for 8 hours at 80 °C and led to HMF in 92% yield.The reaction of 2amino-D-2-deoxyglucose hydrochloride 61 was carried out in mixed solvents with a tellurium buffer at 130°C for 4½ hours and led to 5-hydroxymethylfurfural. Grin et al. 62 studied the conversion of fructose without a solvent leading to HMF.They tested various temperatures and various times of the reaction.The best results were obtained when the reaction lasted 70 minutes and was carried out at 74 °C.Some physico-chemical studies were performed also by Isaacs and Coulson. 63Chmielewski et al. 64 oxidised 2,5-bis-(hydroxymethyl)furan with pyridinium dichromate in dichloromethane to obtain HMF in around 50% yield after 24 hours of the reaction.Tawara et al. 65 studied the mechanism and the chemical behaviour of N-β-Dglucopyranosyl-3-chloro-4-methylaniline in the reaction catalysed by potassium pyrosulfite under microwave irradiation.This reaction also gave HMF in satisfactory yield.
Serious attempts have been made to the isolation of 5-hydroxymethylfurfural from natural products.Numerous scientists tested numerous vegetal materials: Ichikawa 66 carried out the extraction of Ubai drug from Prunus mume, Fernandez 67 extracted it with hot water from Bryothamnion trignetrum.Numata et al. 68 isolated 5-hydroxymethylfurfural from Osmunda japonica, Ayer 69 reported its isolation from malt extract.Shimizu 70 performed the extraction of Campo medicinae and Hsiao 71 obtained HMF from Aralia bipinata.
The problem with the efficient preparation of pure 5-hydroxymethylfurfural is still unresolved.That is why, chemists keep on working on this subject developing new technologies of its synthesis, especially that the field of its application is immense.It is to state that despite numerous methods, which are being reported, no one has found an inexpensive and easy-to-use mode of the preparation of this compound.

Chemical conversions of HMF
From among more than thousand papers concerning HMF, the majority describe the methodology of its synthesis.But it does not mean that studies on its chemical behaviour were neglected -just the opposite, a significant number of serious papers contributed to this topic.These results confirmed the great importance of 5-hydroxymethylfurfural in various branches of the fundamental and applied chemistry.

Reactions of the hydroxymethyl group
The hydroxymethyl group in HMF behaves in a way typical for primary alcohols bearing an aromatic moiety.Thus, it can be compared with benzyl or furfuryl alcohol.

The formation of esters
The acetylation of HMF with acetic acid can lead to triacetates or monoacetates, which was discovered by Fenton 10 and Blanksma. 72But 5-acetoxymethylfurfural 4 was obtained most easily in the reaction of HMF with acetic anhydride. 10,165-Propionoxymethylfurfural 5, a fungicide used much in textile, food and tanning industries 12,[73][74][75] was obtained using two methods 76 .The first required 15 hours of heating of HMF with propionic anhydride, and in the second, propionic acid was reacted with HMF in the presence of sulphuric acid.(Scheme 3) Kiermeyer 8 reported the synthesis of 5-benzoyloxymethylfurfural 6 in the reaction of HMF with benzoyl chloride catalysed by sodium hydroxide.
Recent years brought two patents concerning two methods of the esterification of HMF.The first 77 involved the action of acetic anhydride on HMF in the presence of DMAP as a catalyst; the second 41 exploited the use of sodium salts as catalysts for the reaction of HMF with carboxylic acid anhydrides.

The formation of ethers
Kiermeyer 8 discovered that upon heating HMF in an acidic medium, some 5,5′-diformylfurfuryl ether 7 was found.Chemists started to investigate this problem, after Cram's article 78 appeared, he reported that HMF condensed with diols yielding polyfuran ethers having strong complexing properties.Thus, two efficient methods of ether 7 preparation 50,79 were developed, using DMSO as a solvent.(Scheme 4) Syntheses of other ethers of HMF also were studied.Bredereck 80 obtained 5-(triphenylmethoxy)methylfurfural 8 in the course of the reaction of HMF with trityl chloride in pyridine.The acid-catalysed reaction of HMF with simple alcohols led to corresponding ethers, 17,81 the reaction with ethyleneglycol was catalysed by pyridinium hydrochloride. 82Scheme 4) Some attempts were undertaken to synthesise monosaccharide ethers of HMF.Cottier 83 obtained a mixture of α-and β-annomers of the ether resulting from the condensation of HMF with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide.Lichtenthaler 84,85 synthesised several systems of this kind i.e. α-D-glycosylmethylfurfurals were obtained in 70 % yield.

Scheme 6
Generally a hydroxyl group in primary alcohols is not very reactive towards halogen substitution.In the case of HMF, the reactivity of the hydroxyl group is attributed to the electronwithdrawing character of the furan ring: It has been suggested that the transition state is stabilised by simultaneous overlap of the nucleophile with the central carbon atom and the carbon atom at the 5 position of furan ring: 5-Halomethylfurfurals are extremely reactive, which makes them useful for the synthesis of HMF derivatives.5-Chloro-and 5-bromomethylfurfural both undergo hydrolysis quantitatively to HMF in hot water. 95Both derivatives react also with methanol and ethanol in the presence of barium or calcium carbonates to form corresponding 5-methoxymethylfurfural 13 12,96 and 5ethoxymethylfurfural 14. 12,89 It is intriguing that 5-bromomethylfurfural reacts with sodium cyanide in ethanol to give 5-ethoxymethylfurfural 96 instead of the expected nitrile.(Scheme 7) 5-Chloromethylfurfural undergoes the Friedel-Crafts reaction with benzene and toluene in the presence of aluminium chloride 11 to give 5-benzylfurfural 15 and p-tolylmethylfurfural 16. 5-Methylfurfural 17 was obtained from both the chloro and bromo derivative, when the reaction was catalysed by tin (II) chloride 10 or by zinc powder and acetic acid.The same authors 100 have tested the modification of Adams' procedure of the oxidation with pyridinium chlorochromate (PCC).They oxidised HMF in a mixture consisting of HMF adsorbed on aluminium oxide and ground together with PCC under ultrasonic irradiation to achieve a dialdehyde of 58% yield.
Cottier et al. 101 performed the oxidation of 5-hydroxymethylfurfural with DMSO-potassium dichromate oxidative complex, when ultrasonic irradiation was applied the dialdehyde 19 was obtained in 75% yield.They utilised also trimethylammonium chlorochomate (TMACC) 101 for the oxidation of HMF under sonochemical conditions to obtain the dialdehyde in 72% yield.Van Bekkum 102 and Vinke 103 have developed methods of the selective oxidation of a hydroxymethyl group with noble metal catalysts such as platinum, palladium or ruthenium, that gave excellent yields and selectivities.
Cottier et al. 104 reported the oxidation of HMF with various 4-substituted 2,2,6,6tetramethylpiperidine-1-oxide (TEMPO) free radicals and supporting co-oxidants.They tested a variety of co-oxidants such as calcium hypochlorite, sodium hypochlorite-potassium bromide, copper (I) chloride-oxygen pair, p-toluenesulfonic acid, iodine in alkaline conditions or the electrochemically generated Br radical.Yields varied from 20% to 80% depending on the nature of 4-substituent and of the co-oxidant.The best results were obtained using 4-benzoyloxy-TEMPO with calcium hypochlorite (yield -75%) and 4-acetamido-TEMPO with ptoluenesulfonic acid (yield -81%).( Scheme Cottier et al. 87 has reported also the indirect oxidation of HMF to the dialdehyde 19.HMF was converted into its silyl ethers (5-tert-butyldimethylsyliloxymethylfurfural 10 and 5trimethylsilyloxymethylfurfural 10a) and the oxidation was promoted by N-bromosuccinimide (NBS) in the presence of azoisobutyronitrile (AIBN).A study of the influence of solvent established that the best solvents for this purpose are 1,2-dichloroethane, carbon tetrachloride or dodecane, with the yields of dialdehyde in 76-91% range.(Scheme 10) Scheme 10 3.2.Reactions of the formyl group 3.2.1.Reduction 2,5-Bis-(hydroxymethyl)furan 20 is a compound with a great field of application in the preparation of resins, polymers and artificial fibres. 105It has been synthesised by the reduction of formyl group in HMF catalysed by nickel, copper chromite, platinum oxide, cobalt oxide or molybdenum oxide, and also sodium amalgam. 4

(Scheme 11)
A catalytic hydrogenation of HMF in an aqueous medium in the presence of nickel, copper, platinum, palladium or ruthenium catalysts was investigated. 106The copper or platinumcatalysed reaction resulted in 2,5-bis-(hydroxymethyl)furan as a predominant product, while the application of nickel or palladium caused the hydrogenation of the furan ring.In this case mainly 2,5-bis-(hydroxymethyl)tetrahydrofuran 21 was obtained. 106

(Scheme 11)
There are various reports of studies of reduction with sodium borohydride. 17

Scheme 14
HMF undergoes reaction with compounds bearing an active methylene group.Karashima 16 has carried out the Perkin condensation to afford 5-acetoxymethyl-furfurylideneacetic acid 37. HMF reacts with malonic esters, 12 hydantoin 116 or with acrylonitrile. 117HMF reacts with malonic acid in pyridine in the presence of a catalytic amount of piperidine to yield 5-hydroxymethylfurfurylideneacetic acid 37a, 118 subsequent electrochemical oxidation at a nickel oxidehydroxide anode affords 5-carboxy-2-furfurylideneacetic acid 37b.HMF also undergoes the Horner-Wittig reaction 120 with ethyl diethylphosphonoacetate to give ethyl 5hydroxymethylfurfurylideneacetate 38.(Scheme 15) The Claisen-Schmidt condensation of HMF has also been carried out with acetone, 12 with anthrone, 2 with barbituric acid, 119 with acetophenone 118 to obtain 5-hydroxymethylfurfurylideneacetophenone.This compound was subsequently oxidised to 5-carboxy 118 and 5formyl 100,104 derivatives.α,β-Unsaturated ketones, formed by Claisen-Schmidt condensation reacted with N-substituted hydrazines and guanidine 83  HMF also reacts with alcohols to give acetals.The reaction with 2,2-dimethyl-1,3propanediol 121 gave a cyclic acetal, which is utilised in the preparation of compounds for ionophoresis.Acetals were also obtained by the reaction with ethylene glycol and methanol. 82Scheme 16

Oxidation reactions
It is well known that the formyl group may easily be converted into a carboxylic group -the formyl group on HMF is no exception.The oxidation of the formyl group can be selective leaving the hydroxyl group intact -5-hydroxymethyl-2-furancarboxylic acid 39 is then the exclusive product.Reichstein, 14 oxidised HMF with silver oxide to achieve this conversion.A mixture of silver and copper (II) oxides, 122 and oxygen in the presence of noble metals as catalysts have also been used for the selective oxidation of HMF. 102,103e oxidation of HMF to 2,5-furandicarboxylic acid 40 has been described by Van Bekkum 102 and Vinke 103 who used oxygen and noble metals as catalysts.Morikawa 123 used nitrogen oxides and nitric acid to obtain the diacid 40 in high yield.El-Hajj 44 and Cottier 100 have oxidised HMF with nitric acid.El-Hajj 44 claimed this reaction to be selective i.e. that the diacid 40 was the exclusive product, while Cottier's and co-workers' found that the oxidation of HMF with nitric acid led to the diacid 40 and 5-formyl-2-furancarboxylic acid 41, which was found to be resistant to oxidation under these conditions.The ratio of these two products depended on the reaction conditions.They 100 tested aqueous as well as mixed solvents (such as DMSO or acetic acid), and they studied the chemical behaviour with and without the catalyst and the influence of ultrasound.In each case, the formation of both products was detected.According to Cottier's and co-workers' results 100 and unpublished studies of the author of this article, the formylacid 41 is so resistant to oxidation in acidic conditions owing to the protonation of the carboxylic group leading to, the stabilisation of the formyl group.
HMF undergoes the Canizzaro reaction to form of 2,5-furandicarboxylic acid and 2,5-bis-(hydroxymethyl)furan. 124illwitz 125 performed the decarbonylation of HMF in the presence of calcium acetate and other catalysts to give furfuryl alcohol.

Reactions of the furan ring
Cleavage of the furan ring occurs in acidic medium 126 to give levulinic acid, formic acid and various polymeric substances.Recently, Horvat 127 has proposed the mechanism of HMF degradation.The reaction proceeds via two possible routes (path 'a' and 'b'), which depend on the position of water addition (2, 3 or 4, 5).(Scheme 17) The reaction via mechanism 'a' leads to the formation of 2,5-dioxo-3-hexenal, which undergoes the decomposition to levulinic and formic acids.According to the author of this review, the intermediate A explains well the liberation of formic acid.Reaction through the path 'b' results in the formation of polymers.
The reduction of HMF on Raney nickel results in the formation of 2,5-bis-(hydroxymethyl) tetrahydrofuran. 128The catalytic hydrogenation of HMF 106 in acidic conditions in the presence of platinum or ruthenium leads to 1-hydroxy-2,5-hexenedione 42 and subsequently to 1,2,5hexenetriol 43 (Scheme 18).Photochemical oxidation of HMF in alcohol results first in the formation of endoperoxides.The attack of an alcohol molecule on a formyl group or on a carbon atom '5' in the furan ring leads to the formation of hydroxy-or alcoxybutenolide. 82Hydroxybutenolides are converted into butenolide-γ-ketoacrylic ester, γ-hydroxy-acrylic esters and saturated γ-hydroxy-esters. 82,83Scheme 19) Scheme 18

Polymerisation of HMF
HMF reacts with phenols giving products of condensation or resins depending on pH.These resins react with hexamethylenetetramine (aminoform) with the formation of adhesives utilised as plasticizers. 1295-Hydroxymethylfurfural forms thermoresistant resins in the reaction with ptoluenesulfonamide or butanone. 129,130The reaction of HMF with polyisocyanates 131 gives polyurethanes, which are utilised to the production of infusible and insoluble fibres.According to Gandini, 19 when starch is used as a stabiliser in a phenolate resin synthesis, there is the evidence for HMF formation.The latter reacts subsequently with phenol through its formyl and hydroxyl groups.HMF is also a precursor of a bifunctional furan monomer utilised in the preparation of thermoplastics.El-Hajj 133 performed the electrolysis of HMF at a platinum anode in methanolic solution of tetrabutylammonium perchlorate.The electrooxidation resulted in six products, 2,5-dimethoxy-2-dimethoxymethyl-5-hydroxymethyl-2,5-dihydrofuran 48 was isolated in 11% yield as a predominant product.
Grabowski et al. 134,135 oxidised HMF at a nickel oxide-hydroxide electrode in alkaline aqueous solution of sodium hydroxide.The reaction was carried out in a divided cell, and resulted in formation of 2,5-furandicarboxylic acid 40 in 71% yield, as the exclusive product.
Cottier et al. 136 performed the electrochemical oxidation of HMF resulting in 2,5furandicarbaldehyde 19.The reaction was carried out in a divided cell at a platinum anode in a biphasic (water-dichloromethane) system.Various slightly basic salts such as sodium acetate, sodium hydrogen carbonate, or mono-and disodium phosphates were tested as a supporting electrolyte.Yields varied from 32% to 40%, with 100% selectivity, as the dialdehyde 19 was an exclusive product.The organic layer of the biphasic system acted as a trap to capture the dialdehyde 19 as it was formed protecting it from subsequent oxidation to the diacid.

The synthesis of 2,5-furandicarbaldehyde (FDC)
2,5-Furandicarbaldehyde 19, known by its acronym FDC is one of the most important furan derivatives.There are numerous syntheses of this compound, which may be divided into two groups: methods starting with HMF as a substrate, and those, which utilise other furan derivatives as starting materials.
Pastour and Plantard 137 developed a method for the preparation of FDC (in 36% yield) from furfural via its diethyl acetal, which was reacted subsequently with butyllithium and dimethylformamide. 138Feringa and co-workers 140 treated lithiated furan with DMF to obtain 19 in 80% yield.The same authors 140 converted furfural into its ethylene glycol acetal, which was lithiated with lithium diisopropylamide (LDA) and the organolithium derivative was reacted with DMF to give the dialdehyde 19 in 73% yield.Carpenter and Chadwick 141 lithiated 1,3-dimethyl-2-(2furyl)imidazoline with butylithium and the resulting lithium derivative was converted into the 5formyl derivative by the reaction with DMF.The subsequent hydrolysis led to the dialdehyde 19.Several methods utilize 2,5-bis-(hydroxymethyl)furan 20 as a substrate and the dialdehyde is produced by the oxidation of the former.Oxidizing agents used include chromium trioxide in pyridine 142 (57% yield of FDC), pyridinium dichromate in dichloromethane 64 (65% yield).The same type of oxidation was performed by Oleynik et al., 143 who reported 100% yield.(Scheme 22) FDC has also been synthesised by the oxidation of 2,5-bis-(chloromethyl)furan 50 144,145 or 5chloromethylfurfural 95,117

The chemistry and applications of 2,5-furandicarbaldehyde (FDC)
FDC undergoes all reactions typical for aldehydes.Formation of oximes, has been described by El-Hajj, 44 addition of aliphatic and aromatic amines 152 leads to imines.A method for the reduction of dialdehyde 19 to 2,5-bis-(hydroxymethyl)furan 20 has appeared; 153 several papers have been devoted to its oxidation to 2,5-furandiarboxylic acid 40; 44,95,149,153 especially important papers described the catalytic oxidation with noble metals 102,103 .
The most important conversions of FDC are reactions based on the Wittig reaction. 152,154,155hey are significant from the point of view of organic synthesis -a series of α,β-unsaturated carbonyl compounds as well as vinyl derivatives have been obtained by the functionalisation of one or both formyl groups.(Scheme 23) A number of papers 155,156 have described the synthesis of various ethynyl furan derivatives substituted in positions '2' and '5'.FDC, according to authors is the best starting material for this purpose.

Scheme 25 Scheme 26
The condensation of FDC with 1,3-diaminopropane 164 on Ba +2 template resulted in the macrocycle 61 as the complex of barium.This compound was able to form complexes with such ions as Cu +2 and Cu +1 .
7][168][169][170] They made them by the condensation of FDC with phenylphosphonic acid dihydrazide.Clennan et al. 171 reported results of their work on the chemical behaviour of FDC in the photochemical oxidation with oxygen.They performed 1 H, 13 C and 17 O NMR studies on products of the reaction.
Lumbroso et al. 172 performed IR and dipole moment measurements to establish predominant conformational states.Finally, Scholtz et al. 173 synthesised a radical-anion of FDC and measured its ESR spectrum at various temperatures.
PART C: 2,5-FURANDICARBOXYLIC ACID (FDCA) 2,5-Furandicarboxylic acid (FDCA) 40 was first detected in human urine. 174A healthy human produces 3-5 mg/day.Numerous studies were undertaken to establish the metabolism of this compound and to determine the quantity, which is produced depending on the healthiness of the human.It was demonstrated, for example that the individual quantity of produced FDCA increased after alcohol consumption 174 and after the injection of fructose. 175FDCA was detected also in the blood plasma. 176,177tudies were undertaken to find FDCA outside the human.When glucose was heated under a high pressure, FDCA was found to be one of formed products. 178ugars reacting with amino acids undergo the Maillard reaction.0][181][182] Furan derivatives, among them FDCA, were suggested to be the reason of browning, which is an optical evidence for the Maillard reaction.This suggestion is a good explanation for fruits darkening in the air. 183 Fittig and Heinzelman 187 were the first who performed the regular synthesis of FDCA by the reaction of mucic (galactaric) acid with hydrobromic acid giving a full description of the obtained dehydromucic acid (dehydromucic or pyromucic acid, both are common names of 2,5furandicarboxylic acid).3][194][195][196][197] All these reactions required drastic conditions -the temperature must be over 120 °C, the required time of the reaction should exceed 20 h.Moreover all these methods were not selective 198 (a number of side-products was detected) and were inefficient (yields were less than 50%).Only one method from this group gave the prospectively efficient preparation of FDCA on a large scale. 199Diethyl α,α'-dihydroxymuconate 64 was dehydrated in acidic conditions leading to diethyl 2,5-furandicarboxylate 65 in 95% yield.
[202][203][204] The second class includes reactions of the oxidation of various 2,5-disubstituted furans utilising a variety of inorganic oxidants.Several papers have been published, describing the synthesis of FDCA from furfural [205][206][207][208][209][210][211][212] .Furfural was oxidised to 2-furoic acid with nitric acid and the latter was subsequently converted to its methyl ester.The ester was then undergone the reaction of chloromethylated at position 5 to give methyl 5-chloromethylfuroate.The latter was oxidised with nitric acid to afford dimethyl 2,5-furandicarboxylate, which, after the alkaline hydrolysis gave FDCA in 50% yield.(Scheme 28) It has been suggested 145,207,211 that the reaction is more convenient and efficient when 5chloromethylfuroate is converted into methyl 5-acylmethyl-2-furoate 66 and the latter was oxidised to 2,5-furandicarboxylate.But according to my observation, it prolongs the time of the reaction and does not improve the yield much.

Scheme 28
As mentioned in PART A several significant works deal with the oxidation of 5hydroxymethylfurfural to FDCA.El-Hajj, 44 Blanksma 72 and Cottier et al. 100 performed studies on the oxidation of HMF with nitric acid to obtain the diacid 40.But these methods although efficient, were not selective -the presence of a significant amount of the side-product was detected.This subject was discussed in PART A of this article.5-Chloromethylfurfural also has been oxidised 11 with nitric acid resulting in FDCA in a high yield.5-Hydroxymethyl-2-furoic acid was oxidised with nitric acid too, 44,100 but selectivity of this reaction was similar to that obtained with HMF, but the yield was lower (47%).
Morikawa 123 oxidised HMF with nitrogen dioxide in DMSO and nitric acid in DMSO affording the diacid 40 in 70% yield.
Novitski et al. 153 obtained FDCA by the oxidation of variously 5-substituted 2-furoic acids with sodium hypobromite.The same oxidant, 153 when used in the oxidation of 2,5furandicarbaldehyde 19 led to the formation of FDCA in 83% yield.Some attempts 44,95 were made to oxidise FDC 19 with silver (I) oxide in an aqueous alkaline medium.Both methods turned out to be efficient, especially El-Hajj's one, 44 which afforded FDCA in 80% yield.

Scheme 30
The third group of methods for the preparation of the title compound 40 is based on catalytic reactions of furfural and 5-methyl-furfural as well as of HMF derivatives.
Andrisano 217 reported that potassium 2-furoate, when heated up to 300°C in a nitrogen atmosphere, underwent decarboxylation to furan with simultaneous carboxylation at position Raecke 218 carried out the synthesis of dipotassium 2,5-furandicarboxylate in the course of the pyrolytic reaction of potassium 2-furoate under a pressure of 50 atm and at a temperature of 320°C.However, when the reaction was carried out in the absence of catalysts, the yield was rather lower.When Lewis acids such as CdF 2 , CdCl 2 , CdI 2 or ZnCl 2 were used as catalysts, the efficiency of the reaction improved much and the diacid 40 was obtained in 80% yield.

Scheme 32
When the mixture of silver and aluminium oxides (or silver oxide itself) was utilised as a catalyst 219 , the reaction proceeded through path 'a'.But the application of CuO-Ag 2 O-Cr 2 O 3 /Al 2 O 3 220,221 or CuO-Ag 2 O/Al 2 O 3 catalytic systems favoured the path 'b'.The path 'b' was also preferable, when the mixture of acetates was used. 219,220,222here are not so many papers describing the catalytic oxidation of HMF to the diacid 40.Van Bekkum 102 and Vinke 103 oxidised HMF with noble metals as catalysts; their works are discussed in details in PART A of this article.Lew 122 has patented very efficient methods for the synthesis of FDCA via the catalytic oxidation of HMF.Activated charcoal adsorbed on platinum was used as a catalyst and the author 122 reported the isolation of FDCA in 95% yield.But when the catalytic Pt/C/ CuO-Ag2O mixture was applied, 122 FDCA was obtained in 99% yield.Lew 122 suggested that HMF was oxidised to 5-hydroxymethylfuroic acid with CuO-Ag2O pair and the latter is subsequently oxidised to FDCA with charcoal-on-platinum catalyst.(Scheme 33)

Scheme 33
In conclusion, the synthesis of 2,5-furandicarboxylic acid is much easier than the synthesis of HMF.Several reactions were found to be cheap and efficient enough to be utilised on an industrial-scale.

The chemistry and applications of 2,5-furandicarboxylic acid (FDCA)
2,5-Furandicarboxylic acid is a very stable compound.Its physical properties, such as insolubility in most of common solvents (it is soluble exclusively in DMSO) and a very high melting point (it melts at 342 °C128 ) seem to indicate intermolecular hydrogen bonding as illustrated.100b Despite its chemical stability, FDCA undergoes reactions typical for carboxylic acids, such as halogen substitution to give carboxylic dihalides, 188 the ester formation 190,196 and the formation of amides. 188,196,223All these reactions were elaborated in the beginning of 20 th or at the end of 19 th century.Newer methods have been described by Janda et al., 224 who introduced the synthesis of 2,5-furandicarboxylic dichloride, by the reaction of FDCA with thionyl chloride.The synthesis of diethyl ester 225 and dimethyl ester 223 as well as the amidation 226

have been reported.
There is a group of conversions that illustrates interesting reactivity of this compound.Lyalin and co-workers 227 synthesized 2,5-bis-(trifluoromethyl)furan 68; and Grigorash et al 228 described the preparation of 5-trifluoromethyl-2-furoic acid 69.These two reactions proved that trifluoromethylation of FDCA can be performed selectively -one or both carboxylic groups can be substituted.
The partial fluorisation of the furan ring in FDCA was also performed. 229 The most important group of FDCA conversions is undoubtedly the polymerisation.Malyshevskaya et al, 231 Krieger 232 and Sarzevska et al. [233][234] estbilished the method for the preparation of numerous polyamides having interesting mechanical and physical properties.Polycondensation of FDCA with aromatic diamines gives polyamides in 90% yield. 235itiakoudis 236 obtained polyamides bearing exclusively furan rings and he performed studies demonstrating that these polyamides are extremely thermally resistant.Smay 237 synthesised a wide group of polyamides and polybenzimidazoles bearing furan rings.These polymers can be applied to the preparation of fibres widely utilised in the production of thermally resistant fabrics.9][240][241] Polyamides are also utilised for the preparation of membranes showing osmotic activity 242 .

Scheme 34
Polyesters, have been widely studied.Lukes 243 and Manasek 244 performed the synthesis of polyesters by the condensation of FDCA with ethylene glycol, Akutin 245 and Rodovilova 246 studied its condensation with 4,4′-bisphenol.Products were thermally and mechanically resistant, colourless and fibres had a lower degree of the piling.
Similar properties characterised polyhydrazines synthesised by Frazier and Wallenberg 247 as well as Heertjes and Kok. 238,5-Furandicarboxylic acid was largely applied in pharmacology.It was demonstrated that its diethyl ester had a strong anaesthetic action similar to cocaine. 248Dicalcium 2,5furandicarboxylate was shown to inhibit the growth of Baccillus megatorium spora. 249creening studies on FDCA-derived anilides 73 showed their important anti-bacterial action. 250The diacid itself is a strong complexing agent, 251 chelating such ions as: Ca +2 , Cu +2 and Pb +2 , it is utilised in medicine to remove kidney stones. 252very diluted solution of FDCA in tetrahydrofuran is utilised for preparing artificial veins for transplantation 252 .Treating them with this solution allows the cross-linking of peptide NH2 and OH groups, so that the intracellular matrix of the tissue is formed.The veins are chemically stable and have biophysical and biochemical properties analogous to natural organs, so that few cases of the rejection have been observed.[252][253] At the beginning of this chapter, it was mentioned that FDCA is a chemically stable compound.This property has been well benefited in industry -FDCA as most of polycarboxylic acids is an ingredient of fire foams. Suc foams help to extinguish fires in a short time caused by polar and non-polar solvents.254

Conclusions
I hope that these pages will convince chemists that 5-hydroxymethylfurfural and its derivatives are compounds of great importance in various branches of chemistry.HMF itself is an interesting raw material due to its high reactivity and the polyfunctionality; it is simultaneously a primary aromatic alcohol, an aromatic aldehyde and a furan ring system.Derivatives of HMF have already been utilised in agrochemistry as fungicides, in galvanochemistry as corrosion inhibitors, in cosmetic industry and as flavour agents.
HMF is a good starting material for the synthesis of precursors of various pharmaceuticals, thermo-resistant polymers and complex macrocycles.Among these precursors, one can find 2,5furandicarbaldehyde and 2,5-furandicarboxylic acid; these two compounds are described in detail in this article.The field of their applications is enormous -the dialdehyde offers itself to be the precursor for the synthesis of complexing macrocycles, oxo-porphirines, oxo-annulenes as well as mono-and bis alkenyl and alkynyl furans.The diacid is a building block for numerous polyesters and polyamides; its derivatives were found to be useful in pharmacology.No wonder then, that numerous methods for their preparation have been worked out and published.It is also important that HMF shows a weak cytotoxicity and mutagenicity in human 255 .This fact should be appreciated, considering the high level of the risk during the work with the majority of other useful, multifunctional compounds.
As for the synthesis of HMF, there are still some unresolved problems.However, a high cost of the production of HMF is the most troublesome.Let me be allowed to quote Cottier and Descotes' remark concluding their article 6 entitled "5-Hydroxyemthylfurfural syntheses and chemical transformations".They said there: "...With a more competitive price, HMF should offer new development in diversified fields..." and it is true, because costs, which should be covered just for obtaining HMF limit greatly the progress of studies on this interesting and promising compound.But in my modest opinion, studies on HMF and its derivatives should be continued.