viewonline green chemistry dynamicarticlelinks …szolcsanyi/education/files/chemia...

Green Chemistry Dynamic Article Links

Cite this: Green Chem., 2011, 13, 754

www.rsc.org/greenchem CRITICAL REVIEW

5-Hydroxymethylfurfural (HMF) as a building block platform: Biologicalproperties, synthesis and synthetic applications

Andreia A. Rosatella,a Svilen P. Simeonov,a Raquel F. M. Fradea and Carlos A. M. Afonso*a,b

Received 5th August 2010, Accepted 15th December 2010DOI: 10.1039/c0gc00401d

The biorefinery is an important approach for the current needs of energy and chemical buildingblocks for a diverse range of applications, that gradually may replace current dependence onfossil-fuel resources. Among other primary renewable building blocks, 5-hydroxymethylfurfural(HMF) is considered an important intermediate due to its rich chemistry and potential availabilityfrom carbohydrates such as fructose, glucose, sucrose, cellulose and inulin. In recent years,considerable efforts have been made on the transformation of carbohydrates into HMF. In thiscritical review we provide an overview of the effects of HMF on microorganisms and humans,HMF production and functional group transformations of HMF to relevant target molecules bytaking advantage of the primary hydroxyl, aldehyde and furan functionalities.

1 Introduction

The main source of functionalized carbon skeletons for thefine chemical industry, as well as for thermal and energytransportation, is still based on the fossil-fuel reservoir. However,the increasing price of oil will create new demand for moleculesfrom renewable sources, and it seems likely that biorefineries willplay a more significant role in this respect in the near future.1

The commercial production of wood sugars for ethanolproduction was first considered at the beginning of the 20thcentury.2 Lignocellulose, a very abundant material, comprisesimportant polymers (cellulose, hemicellulose and lignin), ofwhich cellulose and hemicellulose in particular are of highimportance, since they are formed from monomers of glucose(or other types of sugar in the case of hemicellulose), and theycan be used as a carbon source in fermentation processes for theproduction of ethanol.

There are already a considerable range of chemical buildingblocks derived from renewable resources.3 One of these, 5-hydroxymethylfurfural (HMF), plays an important role, becauseit can be obtained not only from fructose but also (more recently)from glucose via isomerisation to fructose, as well as directlyfrom cellulose.

Cellulose is formed by anhydro-D-glucopyranose units linkedby b-1→4-glycosidic bonds, and thus hydrolytic degradation isnecessary to release the sugar monomers. Hydrolytic degrada-

aCQFM, Centro de Quımica-Fısica Molecular and IN–Institute ofNanosciences and Nanotechnology, Instituto Superior Tecnico,1049-001, Lisboa, Portugal. E-mail: [email protected]; Fax: + 351218464455/7; Tel: +35 218419785biMed.UL, Faculdade de Farmacia da Universidade de Lisboa, Av. Prof.Gama Pinto, 1649-003, Lisboa, Portugal. E-mail: [email protected];Fax: +35 1-21-7946476

tion should be controlled to avoid formation of oligosaccharidesand to prevent monosaccharides from reacting at the hightemperatures used.4

In contrast to cellulose, hemicellulose is a polymer formed bydifferent sugar units such as glucose, galactose, mannose, xyloseand arabinose, and it does not form crystalline regions, making itmore amenable to hydrolysis. Additionally, the rate of hydrationdepends on the sugar type, and decreases following the orderxylose > mannose > glucose. Consequently, hemicellulose ishydrolysed faster than cellulose. Whereas dehydration of hexosesproduces HMF, pentoses can lead to production of furfural.4

HMF is very useful not only as intermediate for the produc-tion of the biofuel dimethylfuran (DMF) and other molecules,but also for important molecules such as levulinic acid,2,5-furandicarboxylic acid (FDA), 2,5-diformylfuran (DFF),dihydroxymethylfuran and 5-hydroxy-4-keto-2-pentenoic acid(Scheme 1).

Scheme 1

754 | Green Chem., 2011, 13, 754–793 This journal is © The Royal Society of Chemistry 2011

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online

http://dx.doi.org/10.1039/c0gc00401d



HMF was first reported at the end of the 19th century, whenDull et al.5 described its synthesis by heating inulin with oxalicacid solution under pressure. In the same year, Kiermayer6

reported a similar procedure for HMF synthesis, but startingfrom sugar cane. In the subsequent years, several preparationmethods were reported using homogeneous and heterogeneousacid catalysis, both in aqueous media.7 This topic was first re-viewed in 1951 by Newth et al.,8 and since then several importantreviews have been published, including one by Moye et al.9 onsynthetic methods and industrial applications of HMF. Later,Harris10 described the dehydration reactions of carbohydrates inacidic and basic conditions, including their mechanisms. In 1981two reviews where published, one covering HMF manufacture,11

and other focusing on HMF chemistry.12 In 1990 and 1991,two important reviews were published by Kuster13 and Cottieret al.14 respectively, describing the manufacture of HMF. Morerecently, Lewkowski15 and Moreau et al.16 have reviewed thesynthesis and chemistry of HMF. Corma et al.3a dedicated achapter to the synthesis of HMF in an outstanding reviewof biomass transformations. Woodley et al.17 also summarizedsome processses for the synthesis of HMF, and Zhang et al.18

connected biomass transformations with imidazolium salts, byincluding the synthesis of HMF with ionic liquids as solvents.Some of these reviews are comprehensive, while others justmention HMF chemistry,19 but this area has been progressingvery fast, and over 90 articles have been reported in scientificjournals in 2010.20

In this critical review we provide an overview of the biologicalproperties of HMF, recent developments in the preparation ofHMF from carbohydrates, and synthetic transformations.

2 Formation of HMF during baking

In the bakery industry, the formation of dough starts with amixture of flour, water, yeast and salt, which after fermentationis subjected to high temperatures. During this baking process,the dough undergoes physical and chemical changes. Thetemperature leads to the evaporation of water and the formationof compounds that contribute to flavour and browning. Theseproducts result from Maillard reactions and caramelization. Thefirst consists of a reaction between the carbonyl group of thesugar and the amino group of an amino acid, and generallyoccurs at high temperatures (>50 ◦C) and acidic pH (4–7),and is favoured in foods with a high protein and carbohydratecontent and intermediate moisture content.21 Caramelization isthe oxidation of sugar, and needs more drastic conditions, suchas temperatures above 120 ◦C and more extreme pH (<3 or >9)and a low amount of water.21

These reactions are frequent in bakery products, but also inother foods subjected to high temperatures during processing.The reaction of fructose, lactose and maltose with the aminogroup of lysine to form fructosyl-lysine, lactulosyl-lysine andmaltulosyl-lysine (Amadori products) is characteristic of theearly stages of Maillard reactions, and is responsible fordecreasing the available lysine and food nutritional value. Thus,evaluation of these compounds has been suggested to workas control parameters for assessment of the quality of foods.22

However, other products can be formed, and there are severalexamples in the literature of the degradation of the sugar in

HMF, for instance, during heating of milk, which has a highconcentration of lactose and lysine-rich proteins.23 Under acidicconditions, lactulosyl-lysine can suffer 1,2-enolization via 3-deoxyosulose to form bound HMF. However, isomerisationand degradation of lactose (the Lobry de Bruyn–van Ekensteintransformation) also accounts for the formation of HMF.Quantification of bound HMF can be used to assess the extent ofthe Maillard reaction in foods. Morales et al. have removed thefree lactose from milk samples and quantified HMF releasedfrom oxalic acid degradation of lactulosyl-lysine compounds,using reversed-phase HPLC. This study demonstrated that thismethod can be used to determine the extent of the Maillardreaction; however, they also showed that this reaction is a minorroute for sugar degradation. Other techniques, such as the 2-thiobarbituric acid (TBA) method, widely applied in dairies,can also be used to quantify HMF, but it is less suitable sinceother aldehydes can take part in the reaction.24

Many other studies have been published, but HPLC seems tobe the chosen method for HMF determination.25 Solubilisationof the ground food sample in water and use of trichloroaceticacid (as a clarifying agent), was used to eliminate interferenceduring HPLC determination of HMF in cookies.25b HMFdetermination has also been used as a parameter to evaluateheat effects during manufacture of cereal products.26 Ramırez–Jimenez et al. have reported formation of HMF during browningof sliced bread, and increasing amounts were detected withincreasing heating time (14.8 mg kg-1 and 2024.8 mg kg-1 with 5or 60 min toasting time, respectively).26c Fallico et al. have alsoreported the effect of the temperature in the HMF formationduring the roasting of hazelnuts, and they also studied theeffect of the oil in this mechanism. Defatted crushed hazelnutsproduced less HMF during roasting (2.2 mg kg-1 at 150 ◦Cfor 60 min) than crushed hazelnuts (8.0 mg kg-1 at 150 ◦C for60 min), and addition of 10% water to the defatted crushedhazelnuts led to an increase of HMF of approximately 32%.Additionally, increasing the temperature to 175 ◦C producedan increase in HMF concentration, as expected (66.5 mg kg-1

for crushed hazelnuts and 17.9 mg kg-1 for defatted crushedhazelnuts), even when toasted for 30 min.27 Furthermore, studieshave also demonstrated that formation of HMF decreases withthe increase of humidity, and that fructose is more efficientlydegraded in this furfural derivative than glucose.28

3 Biological properties

3.1 Effects of HMF on the growth of microorganisms

The use of hemicellulose in fermentation as a carbon source,and the consequent generation of HMF, has created a demandfor HMF-resistant microorganism strains (Table 1).

Several studied strains of Saccharomyces cerevisiae were foundto be quite tolerant to HMF; however, results varied substan-tially within the studied microorganisms: 1) addition of 4 gL-1 of HMF to an anaerobic fermentation with Saccharomycescerevisiae CBS 8066 caused a decrease in the carbon dioxideevolution rate, and the growth rate was significantly affected.HMF was metabolized by the yeast but this process stoppedafter exhaustion of glucose, with the consequent end of ethanolproduction;29 2) a lower concentration of 1.5 g L-1 HMF did

This journal is © The Royal Society of Chemistry 2011 Green Chem., 2011, 13, 754–793 | 755

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 1 Effect of HMF on the growth and/or ethanol production during fermentation using different strains of microorganisms

Microorganism HMF (g L-1) Result

Saccharomyces cerevisiae CBS 806629 4.0 Growth did not decrease, but reached a plateau after faster consumptionof glucose, with consequent ceasing of ethanol production

Saccharomyces cerevisiae TMB 300130 1.5 No effect on ethanol productionSaccharomyces cerevisiae ATCC 21123931 <2.5 Growth was not significantly affected

3.8 Long lag phase in the growth curve of about 24 hSaccharomyces cerevisiae NRRL Y-1263231 2.5 Growth greatly affected

3.8 No growthSaccharomyces cerevisiae TMB 340023b 7.6 Decreased glucose consumption and production rate of ethanolPichia stipitis NRRL-Y-712431 2.5 Growth not significantly affected

3.8 No growthRhodosporidium toruloides Y433 1.9 Growth was not significantly affected

not have any effect on ethanol production during the anaerobicfermentation of xylose by S. cerevisiae TMB 3001;30 3) studieswith S. cerevisiae ATCC 211239 demonstrated that cell growthwas not significantly affected at a HMF concentration below2.5 g L-1, but at 3.8 g L-1, a long lag phase in the growthcurve (approximately 24 h) appeared;31 4) S. cerevisiae NRRLY-12632 was greatly affected at a concentration of 2.5 g L-1, andno growth was detected at a concentration of 3.8 g L-1;31 and5) larger amounts of HMF (7.6 g L-1) were also tested in ananaerobic fermentation with S. cerevisiae TMB 3400, and ledonly to a 50% decrease of glucose concentration within 24 h(compared to the control, in which the glucose had already beenused up), with a consequent decrease of the production rate ofethanol.23b

A different yeast – Pichia stipitis NRRL-Y-7124 – was alsotested, and growth was not significantly changed in the presenceof 2.5 g L-1 HMF; however, it was impaired at a concentrationof 3.8 g L-1.31 A different study performed with this last strainrevealed that tolerance to HMF improved in stationary phasecultures and was greater in the presence of glucose ratherthan xylose and, regardless of the carbon source, amino acidenrichment of the culture medium enhanced the ability of cellsto resist HMF exposure.32 Rhodosporidium toruloides Y4 hasalso been investigated, and addition of 1.9 g L-1 HMF wasdemonstrated not to change significantly substrate consump-tion, biomass concentration and lipid content. This yeast straincan accumulate intracellular lipids as high as 60% of its cell dryweight in the presence of glucose, and the corresponding fattyacids are similar to those of vegetable oil, making it an alternativefor production of biodiesel.33 Two strains of Escherichia coli(LY01 and KO11) have also been studied, and 4.0 g L-1 HMFterminated the growth of both within 24 h.34 Additionally, HMFat a concentration of 0.71 g L-1 was added to a culture ofTrichosporon cutaneum 2.1374, but it did not produce an obviousinhibitory effect on cell growth and lipid production.35

3.2 Effects of HMF in humans

As mentioned previously, some food can contain considerableamounts of HMF, and some examples are dried fruits,36

coffee,36 cereals26d,36b and baking products.26b,26d,36–37 Addition-ally, HMF has also been detected in medicinal fluids adminis-tered intravenously.38 Due to the daily consumption of thesefoods, the estimated daily intake of HMF is approximately30–150 mg per person.39 Studies with rats and dogs showed

that HMF can be toxic if administered at doses of 75 mgkg-1 body weight.19d Consequently, several studies have beenconducted in an attempt to investigate the effect of HMF inhumans.

To assess the effect of HMF in humans, several in vitro andin vivo assays have been performed. The mutagenic effect hasbeen assessed by the Ames test, which studies the potentialof the compound to make possible the growth of histidine-deficient bacterial strains plated without a histidine supplement.In these tests, HMF was found to be not mutagenic orweakly mutagenic.40 Brands et al. have tested heated mixturesof sugar-casein using the Ames test, and have concludedthat mutagenicity is related to the extent of the Maillardreaction, and varied with the type of sugar, fructose beingmore mutagenic than glucose (the reason being the differentreaction mechanisms).41 Furthermore, disaccharides were lessmutagenic than monosaccharides, because the first induced lessmutagenic compounds.41 However, the compounds responsiblefor this mutagenicity were not identified, but results were weakcompared to the chemical mutagen 4-nitroquinoline-N-oxide,used as positive control.41 Additionally, the viability of thehuman hepatocyte cell line-HepG2 in the presence of HMFwas not significantly affected (a concentration of 38 mM wasnecessary to reduce viability in about 50%), and induction ofmicronucleus formation in this cell line was not detected either.40a

Moreover, the presence of HMF protected the human livercell line-LO2 against exposure to hydrogen peroxide, becauseit prevented nitric oxide production, caspase-3 activation andarrest of the cells in the S-phase of the cell cycle.42

In accordance with this data, HMF was present in processed‘Fructus Corni’ used by the Chinese to invigorate the liver andkidney,42 and the same compound was also detected in processedsteamed ‘Rehmanniae Radix’, a natural remedy in Chinesemedicine used in several diseases such as anemia and diabetes.43

HMF has also been reported to be a promising candidate fortherapy of sickle cell disease, since it binds efficiently to sicklehaemoglobin, inhibiting sickling of red blood cells.44

On the other hand, contradictory results have been obtainedin other experiments. The human colon cancer cell line CaCo-2, the human epithelial kidney cell line HEK 293, the mouselymphoma cell line L5178Y, the Chinese hamster cell lineV79 and the human sulfotransferase SULT1A1 expressing V79displayed DNA damage in the presence of HMF.45 Additionally,a derived V79 cell line (V79-hCYP2E1-hSULT1A1) had a higherfrequency of sister chromatin exchange (SCE) in the presence of


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


HMF.46 However, other reports demonstrated HMF-inducedDNA damage just at high concentrations and fail to correlate5-HMF-induced DNA damage with sulfotransferase-SULT1A1activity. Furthermore, HMF at a concentration of 23.71 mg mL-1

induced 50% mortality of nauplii in the brine shrimp bioassay,47

while thermolyzed sucrose (which contains 1% HMF), whenadministered to female rats treated 1 week previously with thecolon carcinogen azoxymethane (AOM), enhanced the growthof the colonic aberrant crypt foci.48

One of the hypotheses attempting to explain these differ-ent effects is the possibility that HMF is metabolized to amore harmful molecule such as 5-sulfooxymethylfurfural (5-SMF),49 which can be produced through HMF sulfonation bysulfotransferases.50 The fact that the Ames test for 5-SMF givesa positive result for Salmonella thyphimurium TA10049 seemsto give strength to this idea. 5-SMF was also demonstratedto exhibit a higher skin tumor initiating activity than HMFafter its application on mouse skin.49,51 More recently, 5-SMFwas quantified in vivo after intravenous injection of HMF inthe mouse.52 A cytotoxic effect of 5-SMF was also reportedin recombinant embryonic kidney cells: 5-SMF was shown tobe a substrate for the organic anion transporters OAT1 andOAT3, and to decrease by 80% and 40% (respectively) theuptake of the substrates p-aminohippurate and estrone sulfateat a concentration of 1 mM, which indicates that 5-SMF caninterfere with the transport of organic anions into renal proximaltubule cells, leading to kidney damage.53 Moreover, other studiesdid not demonstrate the presence of the sulfate metabolite in theurine of male F344 rats and B6C3F1 mice after administrationof HMF (5, 10, 100, 500 mg kg-1), being about 60–80% of HMFexcreted in the urine.54 None of this metabolite was detected inhuman subjects after consumption of dried plums and/or driedplum juice, although four other metabolites were detected: N-(5-hydroxymethyl-2-furoyl)glycine, 5-hydroxymethyl-2-furoic acid,(5-carboxylic acid-2-furoyl)glycine and (5-carboxylic acid-2-furoyl)aminomethane.36b In addition, HMF and 5-SMF wereboth tested in Min/+ mice (heterozygous for a mutation in thetumor suppressor gene Apc), and despite increasing the numberof adenomas in the small intestine, they had no effect on theirsize, compared with the control mice, and thus were classified asweak intestinal carcinogens.55

4 HMF synthesis

This section will focus on the manufacture of HMF, takinginto account reaction conditions, such as solvents, substratesand their concentrations, as well as catalysts and their reuse.Additionally, the mechanisms of the different synthetic method-ologies will be discussed.

Several catalysts have been reported for the dehydration ofcarbohydrates, and Cottier et al.14 organize them into fivegroups: organic acids, inorganic acids, salts, Lewis acids, andothers. In recent years, carbohydrate dehydration catalysts haveundergone a remarkable process of evolution, and severalnew catalysts have been reported. Here, we group dehydrationreactions by the catalysis type: acid catalysis (homogeneousliquid, heterogeneous liquid–liquid, solid-liquid and gas-liquid)and metal catalysis.

∑ Problems in HMF synthesis. HMF is synthesized mainlyby the dehydration of monosaccharides, requiring the loss ofthree water molecules. Disaccharides or polysaccharides, suchas sucrose, cellobiose, inulin or cellulose, can be used as startingmaterials, but hydrolysis is necessary for depolymerisation.Sucrose hydrolysis is more efficiently catalyzed by a base;however, dehydration of the monomers is catalyzed by acids.This introduces a problem, namely that the formation of HMFby dehydration is a very complex process due to the possibilityof side-reactions. Antal et al.56 reported the possible side-products formed by decomposition of fructose in water at hightemperatures, being products of isomerisation, dehydration,fragmentation and condensation. The mechanism for fructosedehydration reaction is not clear, and two different pathwayshave been proposed for the formation of HMF (Scheme 2).15,56

Scheme 2 15.

∑ Glucose vs. Fructose. Glucose (aldose) reactivity is lowerthan fructose (ketose), and this fact has been explained by themuch lower abundance of acyclic glucose compared to acyclicfructose.13,57 Glucose can form a very stable ring structure, sothe enolisation rate in solution is lower than fructose, whichforms less stable ring structures.13 Since enolisation is therate-determining step for HMF formation, fructose will reactmuch faster than glucose. On the other hand, fructose formsequilibrium mixtures of difructose and dianhydrides, and thusthe most reactive groups are internally blocked, forming smalleramounts of by-products.13 Glucose forms true oligosaccharideswhich still contain reactive reducing groups, resulting in a greaterrisk of cross-polymerisation with reactive intermediates andHMF.13

∑ HMF isolation methods. In most of the reported studies ofHMF synthesis, the HMF was obtained in solution, and the yielddetermined by HPLC or GC. However, it is important not onlyto optimize the synthesis of this compound, but also to developan efficient isolation method. HMF is not easy to extract fromaqueous phase, since the distribution coefficient between theorganic and the aqueous phase is not favourable.13,58 However,this problem has been overcome by the use of organic solventssuch as MIBK (methyl isobutyl ketone),59,60 DCM,60c ethylacetate,61 THF,62 diethyl ether,63 and acetone,64 which have beenreported to be efficient extraction solvents. These could improvethe synthesis of HMF, since they may avoid the formation of


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 2 Conversion of carbohydrates to HMF using homogeneous catalysis by mineral or organic acidsa

Reaction conditions Post-reaction details

Entry(ref.)

Biomasssource Solvent Catalyst

Temp.(◦C) Time

Conver-sion (%)

HMFselectivity (%)

Isolation/determi-nation method

Catalyst, reactionmedium reuse

157 Fructose H2O PTSA 88 3.3 h — ~20 HPLC —257 Fructose 1:1 H2O–PEG 4000 PTSA 88 3.3 h — ~45 HPLC —357 Fructose H2O–CrCl3 PTSA 88 3.3 h — ~20 HPLC —469 Fructose 1:1 Fructose–PEG

6000HCl 180 10 s — 65 — —

570 Fructose Ethylene glycoldimethyl ether

H2SO4 200 3.3 h 100 70.0 GC Solvent reused

671 Fructose(27% aq.sol.)

H2O HCl 200(MW)

1 s 52 63 HPLC —

771 Fructose(27% aq.sol.)

H2O HCl 200(MW)

60 s 95 55 HPLC —

872 Fructose [BMIM][Cl] H2SO4 120 4 h 100 85 HPLC —975 Fructose H2O HCl

(microreactor)200(17bar)

1 min 97 59 HPLC —

1075 Fructose H2O HCl(microreactor)

185(17bar)

1 min 71 75 HPLC —

1175 Fructose(10 wt.%)

1:2 H2O–DMSO /MIBK–2-butanol

HCl(microreactor)

185(17bar)

1 min 100 72 HPLC —



HCl(microreactor)

185(20bar)

1 min 98 85 HPLC —



HCl(microreactor)

185(20bar)

1 min 98 81 HPLC —

1476 Fructose 4:6Fructose–cholinechloride

PTSA 100 30 min — 67 EtOAcextraction/HPLC

—

1576 Inulin 5:5Fructose–cholinechloride

PTSA 90 1 h — 57 EtOAcextraction/HPLC

—

1676 Glucose 4:6Fructose–cholinechloride

CrCl2 110 30 min — 45 EtOAcextraction/HPLC

—

1776 Sucrose 5:5Fructose–cholinechloride

CrCl2 100 1 h — 62 EtOAcextraction/HPLC

—

a PTSA, p-toluenesulfonic acid; DMSO, dimethyl sulfoxide; [BMIM][Cl], 1-butyl-3-methylimidazolium chloride; MIBK, methyl isobutyl ketone;MW, microwave irradiation.

by-products, such as soluble polymers or humins, amongothers.65 Polar organic solvents, such as DMSO or DMF,65a,66

have a high boiling point, and due to the reactive nature of HMFat high temperatures,60c,67 distillation is undesirable. Recently, itwas possible to isolate HMF by extraction with a low-boiling-point solvent in the presence of ionic liquids.61c,68 In the lastfew years, several improvements have been achieved in this field,but more efficient separation techniques need to be developedin order to make synthesis economically viable for larger-scaleproduction.

4.1 Acid-based catalysis

4.1.1 Homogeneous catalysis. In 1986 Van Bekkum et al.57

studied the dehydration of fructose to HMF in acidic medium,and observed that the carbohydrate concentration affected theHMF yield. For higher fructose concentrations the HMF yield

decreases, due to the formation of larger amounts of humins,likely a result of reactions with HMF, fructose and theirintermediates (Table 2, entry 1). The addition of metal chlorides(Cr(III) or Al(III)) to the HCl-catalyzed dehydration improvedthe yield of HMF (Table 2, entry 3), but HMF rehydrationwas also enhanced.57 The formation of HMF was also affectedby the pH, or the nature of the acid, but on the other hand,the rehydration of HMF was not, so an increase of the acidconcentration led to an increase in yield. The influence of waterwas also studied, performing the reaction in PEG. This was notan ideal solvent due to the possibility of the formation of HMF–PEG ethers that induce the formation of levulinic acid, althoughthe yield of HMF could be improved by 45%.

HMF synthesis has already been reported using PEG 6000as solvent.69 A mixture of PEG and fructose (1:1 w/w) becamehomogeneous after heating and addition of a small amountof acid. Passage of this mixture through a tubular reactor, at


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


high temperatures (120–200 ◦C), led to reasonable HMF yields(Table 2, entry 4) with shorter reaction times, but ethers fromHMF and PG-600 reaction were also obtained. The isolationof the product from this solvent was a drawback, due to theinstability of HMF at high temperatures.

One synthesis of HMF involved dissolving 1,2:4,5-di-o-isopropylidene-b-D-fructopyranose in ethylene glycol dimethylether (EGDE) containing water and sulfuric acid as a catalyst.70

As shown in Scheme 3, the first step consists of the transforma-tion of fructose into a fructose acetonide derivative, followed byrapid dehydration to give HMF. The main advantages of thismethod is that high reactant concentrations can be achievedusing cheap and easily regenerated solvents, and the reactivehydroxyl groups of fructose which induce HMF instability areblocked at an earlier stage of the dehydration. However, foreconomic reasons, it would be preferable to use a method thatdirectly uses a biomass feedstock rather than another substratethat needs derivatization.

Scheme 3 70.

Having three main goals in mind – an acid catalysed reactionin 100% water, with HCl as the catalyst, and a feedstock of highlyconcentrated aqueous fructose – Hansen et al.71 reported themicrowave-assisted dehydration of fructose to HMF (Scheme 4).In this work, aqueous fructose (27 wt%) was irradiated withmicrowaves for 1 s (200 ◦C), producing a conversion of 52%with an HMF selectivity of 63%. For longer irradiation periods(60 s), 95% conversion was achieved, but with a lower HMFselectivity, 55%, (Table 2, entries 6 and 7). Consequently, a slightimprovement was achieved compared to conventional heating(for example Table 3, entry 2160b).

Scheme 4 71.

Almost complete conversion of fructose, glucose and mannosewere observed in the presence of a Brønsted acid, H2SO4 at120 ◦C within 4 h, in an ionic liquid [BMIM][Cl] (1-butyl-3-methylimidazolium chloride).72 In the presence of fructose,

the main product was HMF (Table 2, entry 8), with 85%yield. The authors reported that a similar result was obtainedwhen the reaction was carried out without H2SO4. For glucoseand mannose, although the conversion was almost complete,the main product formed was not HMF, confirming thatdehydration of ketoses is quicker than aldoses.15 HMF stabilityin [BMIM][Cl]/H2SO4 was studied, resulting in almost completerecovery of HMF (7% conversion and 1% solid residuesformation). Other stability studies of HMF in [BMIM][Cl] undervarious reaction conditions were performed,73 also leading toalmost complete HMF recovery, showing that HMF is stablein [BMIM][Cl]. When HMF and glucose mixtures were tested([BMIM][Cl]/H2SO4 at 120 ◦C after 4 h), an increase of HMFconversion (48%) and almost complete glucose conversion (96%)were observed. An increase of the solid residues was also noticed,compared with the solid formed in the presence of just glucose.This indicates that HMF in these conditions can react withmonosaccharides or monosaccharide degradation products.

The use of microreactors can have advantages when comparedwith conventional batch reactions, including better control ofreaction conditions (temperature, pressure and residence time),improved safety, and portability.74 HCl-catalyzed dehydrationof fructose in pure aqueous solutions was conducted in acontinuous microreactor process (Table 2, entries 9–13).75 Whenthis process was compared with an HCl-catalyzed dehydrationof fructose in aqueous solution with microwave heating (Table 2,entries 6 and 7, 95% conv. with 55% HMF selectivity), at200 ◦C the HMF selectivity and fructose conversion were slightlyimproved (Table 2, entry 9, 97% conv. 59% HMF selectivity,200 ◦C). This result was further improved by decreasing thetemperature to 185 ◦C, which led to HMF with 75% selectivityand 71% fructose conversion (Table 2, entry 10). To furtherimprove the HMF selectivity the dehydration of fructose wascarried out in aqueous solutions using DMSO as co-solventand methyl isobutyl ketone/2-butanol as the extraction agent.A higher fructose conversion (up to 98%) was achieved as wellas a higher HMF selectivity of 85% (Table 2, entry 12). A highfructose concentration of 50 wt.% resulted in 98% conversion,with an 81% HMF selectivity (Table 2, entry 13).

Highly concentrated melt systems consisting of choline chlo-ride (ChCl) and up to 50 wt% of carbohydrates were tested inthe dehydration reaction with different catalysts.76 For fructoseand inulin the best catalyst was PTSA (p-toluenesulfonic acid)(Table 2, entries 14 and 15), and for glucose and sucrose the bestcatalyst was CrCl2 with HMF yields of 45 and 62% respectively(Table 2, entries 16 and 17). Although some of the reactionstested were analysed by HPLC to determine the HMF yield,a method of extraction and evaporation with ethyl acetate wasreported. A preliminary ecological evaluation was made and therecyclability of the process is being studied.

Transformation of D-glucose was followed in a flow reactor,and in high-pressure water and D-fructose, 5-HMF, furfuraland 1,2,4-benzenetriol (BTO) yields were quantified.77 Glucoseconversion increased with the temperature (being about 100%at 400 ◦C) and with the pressure. However, the yield of D-fructose was higher at 350 ◦C than 400 ◦C, and a decreaseof the pressure enhanced its yield. Longer residence times ledto higher 5-HMF yield, but the effect was more evident at350 ◦C than at 400 ◦C. As a result, the highest 5-HMF yield


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 3 Conversion of carbohydrates to HMF in heterogeneous (liquid–liquid) catalysis by mineral or organic acidsa


Entry(Ref.) Biomass source Solvent Catalyst

Temp.(◦C) Time

Conver-sion (%)

HMF selec-tivity (%)

Isolation/deter-mination method

160d Fructose (30 wt.%) 7:3 (8:2H2O–DMSO)–PVP / 7:3MIBK–2-butanol

HCl 200 3 min 89 85 MIBK–2-butanol(7:3) extraction

260d Fructose (50 wt.%) 7:3 (8:2H2O–DMSO)–PVP / 7:3MIBK–2-butanol

HCl 200 3 min 92 77 MIBK–2-butanol(7:3) extraction

360c Glucose (10 wt.%) 4:6 H2O–DMSO / 7:3MIBK–2-butanol

HCl 170 10 min 43 53 MIBK–2-butanolextraction

460c Glucose (10 wt.%) 5:5 H2O–DMSO / 7:3MIBK–2-butanol

HCl 170 17 min 50 47 MIBK–2-butanolextraction

560c Glucose (10 wt.%) 3:7 H2O–DMSO / DCM — 140 4.5 h 62 48 DCM extraction660c Fructose (10 wt.%) 5:5 H2O–DMSO / 7:3

MIBK–2-butanolHCl 170 4 min 95 89 MIBK–2-butanol

extraction760c Fructose (10 wt.%) 3:7 H2O–DMSO / DCM — 140 2 h 100 87 DCM extraction860c Inulin (10 wt.%) 5:5 H2O–DMSO / 7:3


extraction960c Inulin (10 wt.%) 3:7 H2O–DMSO / DCM — 140 2.5 h 100 70 DCM extraction1060c Sucrose (10 wt.%) 4:6 H2O–DMSO / 7:3


extraction1160c Sucrose (10 wt.%) 3:7 H2O–DMSO / DCM — 140 4.5 h 82 62 DCM extraction1260c Cellobiose (10 wt.%) 4:6 H2O–DMSO / 7:3


extraction1360c Cellobiose (10 wt.%) 3:7 H2O–DMSO / DCM — 140 9.5 h 85 45 DCM extraction1460c Starch (10 wt.%) 4:6 H2O–DMSO / 7:3


extraction1560c Starch (10 wt.%) 3:7 H2O–DMSO / DCM — 140 11 h 91 40 DCM extraction1660b Fructose (30 wt.%) 35% aq. NaCl–1-butanol HCl 180 — 64 84 1-Butanol extraction1760b Fructose (30 wt.%) 35% aq. NaCl–2-butanol HCl 180 — 71 79 2-Butanol extraction1860b Fructose (30 wt.%) 35% aq. NaCl–1-hexanol HCl 180 — 78 72 1-Hexanol extraction1960b Fructose (30 wt.%) 35% aq. NaCl–MIBK HCl 180 — 72 77 MIBK extraction2060b Fructose (30 wt.%) 35% aq. NaCl /

toluene–2-butanolHCl 180 — 74 88 Toluene–2-butanol

extraction2160b Fructose (30 wt.%) 35% aq. NaCl HCl 180 — 59 57 HPLC2278 Fructose (30 wt.%) Sat. aq. NaCl–1-butanol HCl 180 35 min 87 82 HPLC2378 Fructose (30 wt.%) Sat. aq. KCl–1-butanol HCl 180 15 min 89 84 HPLC2478 Fructose (30 wt.%) Sat. aq. CsCl–1-butanol HCl 180 15 min 92 80 HPLC2578 Fructose (30 wt.%) 1-Butanol HCl 150 35 min 93 69 HPLC2678 Fructose (30 wt.%) Sat. aq. NaCl–1-pentanol HCl 150 35 min 75 77 HPLC2778 Fructose (30 wt.%) Sat. aq. NaCl–2-propanol HCl 150 35 min 39 80 HPLC2878 Fructose (30 wt.%) Sat. aq. NaCl–2-butanol HCl 150 35 min 67 85 HPLC2978 Fructose (30 wt.%) Sat. aq. NaCl–2-pentanol HCl 150 35 min 83 82 HPLC3078 Fructose (30 wt.%) Sat. aq. NaCl–2-butanone HCl 150 35 min 84 82 HPLC3178 Fructose (30 wt.%) 2-Butanone HCl 150 35 min 92 73 HPLC3278 Fructose (30 wt.%) Sat. aq. NaCl–THF HCl 150 65 min 53 83 HPLC3378 Fructose (30 wt.%) THF HCl 150 35 min 95 71 HPLC3478 Fructose (30 wt.%) Sat. aq. NaCl–THF HCl 160 50 min 88 89 HPLC3580 Glucose H2O 1. Glucose

isomerase–sodiumtetraborate;2.HCl–NaCl–1-butanol

190 45 min 88.2 63.3 HPLC

a MIBK, methyl isobutyl ketone; PVP, poly(1-vinyl-2-pyrrolidinone); THF, tetrahydrofuran; DMSO, dimethyl sulfoxide.

(7%) was achieved at 350 ◦C, 80 MPa and 1.6 s residence time.The yield of other products (furfural and BTO) also increasedwith the temperature, pressure and residence times. The increaseof solution density increased the rate of dehydration to 5-HMF and hydrolysis reaction of 5-HMF. High temperatures,high solution densities and short residence times seemed to beadvantageous for the selective synthesis of 5-HMF, preventingformation of BTO. High temperatures, high solution density

and long residence times favoured the production of BTO andfurfural. The authors suggested another pathway for formationof furfural that is not derived from 5-HMF, since both areincreased when the residence time increases.77

4.1.2 Heterogeneous catalysis – liquid–liquid. Roman–Leshkov et al.60d described an improved method of fructosedehydration at high concentrations (30–50 wt.%), with an acid


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


catalyst, involving the addition of modifiers in both reactionphases (Fig. 1). As reported before,57 high concentrations offructose increase the amount of side-products. To overcomethis problem, the authors added to the aqueous phase a polaraprotic solvent (DMSO or 1-methyl-2-pyrrolidinone (NMP))and/or a hydrophilic polymer (poly(1-vinyl-2-pyrrolidinone)(PVP)), improving the HMF selectivity (Table 3, entries 1 and2). In this work methyl isobutyl ketone (MIBK) was used asthe extraction solvent, and the addition of these modifiers tothe aqueous phase increased HMF solubility in the aqueousphase, hampering the extraction process with methyl isobutylketone (MIBK). However, adding 2-butanol to the organic layerraised HMF solubility, improving the extraction process. Severalmineral acids were tested (H2SO4, H3PO4 and HCl), HCl havingthe best HMF selectivity.

Fig. 1

Further work was carried out60c by the same authors, inwhich they optimized the method for dehydration of glucose,achieving up to 53% HMF selectivity (Table 3, entries 3 and 4).In this work HCl was used as the acid catalyst, in an aqueousphase with DMSO as co-solvent, and an extracting phase withMIBK–2-butanol, or dichloromethane. The best conditionsachieved for the dehydration of glucose were applied to othersaccharides such as inulin (a polyfructan), starch (a polyglucan),cellobiose (a glucose dimer) and sucrose (a disaccharide ofglucose and fructose), just by adjusting the pH and DMSOcontent (Table 3, entries 6–15). The main problem observed wasthe carry-over of DMSO to the organic phase, and thereforeHMF separation from the DMSO at the end of the process wasnecessary. This is very complicated due to the reactive nature ofHMF at high temperatures,60c,67 meaning that high-temperaturedistillation is not possible. Therefore, separation techniques needto be developed to make these efficient methods of synthesiseconomically viable for larger-scale production.

Roman–Leshkov et al.60b reported the acid-catalysed dehydra-tion of fructose in a biphasic reactor, using different extractionsolvents (Table 3, entries 16–21). Since HMF selectivity increaseswith the efficiency of the extraction solvent, NaCl was addedto the aqueous phase to increase the extraction efficiency bya salting-out effect, and 1-butanol was used as the extractingsolvent. The advantages of this method are that no DMSOwas added to the aqueous phase, because the addition ofthe salt prevents the system from becoming single-phase, ashappened when 1-butanol was the extraction solvent in a systemwithout NaCl. On the other hand, 1-butanol is a biorenewablesolvent that can be obtained by biomass-derived carbohydratefermentation.60b The fructose concentrations were higher thanprevious results,60c but the conversion and HMF selectivity werenot so good (Table 3, entries 6 vs.16). With this system is possible

to recycle the water, NaCl, a fraction of 1-butanol, and 58% ofthe HCl. The authors did not report the isolation of HMF fromthe extraction solvent.

To improve this biphasic reaction system with a salting-outeffect, different classes of C3–C6 extraction solvents, such asaliphatic alcohols, ketones, and ethers were tested.78 Solventswith four carbon atoms (C4) generated the highest HMFselectivity values within each solvent class. These solventsshowed the highest affinity for HMF, coupled with low watermiscibility at the reaction temperature (Table 3, entries 28and 30–32). The increase of temperature induces higher HMFselectivity, but on the other hand, the reaction temperature hasto be sufficiently low to avoid solvent degradation reactions.Thus, the reactions were performed at 180 ◦C. Using 1-butanolas the extraction solvent, the effect of different salts on thedehydration reaction was studied. It was shown that KCl andNaCl generated the best combination of extracting power andhigh HMF selectivity (Table 3, entries 22–24).78 The authorsshowed that HMF selectivity could be improved using saturatedNaCl solutions, but the conversion of fructose was higher whenno salt was added to the aqueous phase (Table 3, entries 22vs.25). However, the authors did not provide details about theisolation of the final product.

One of the main routes for the transformation of glucoseto HMF involves an isomerisation step to fructose, followedby fast dehydration.60a,63,66,79 In view of this, Huang et al.80

reported the synthesis of HMF using an enzymatic glucoseisomerisation to fructose with a borate-assisted isomerase,followed by dehydration in an acidic medium (Scheme 5) with 1-butanol as the extraction solvent. With this system, a 88.2%sugar conversion and 63.3% HMF selectivity were obtainedwithin 45 min (Table 3, entry 35). A low percentage of solubleby-products (levulinic and formic acids) was formed in this case,but for high reaction times, the HMF yield started to decrease,suggesting the formation of humins.

Scheme 5 80.

A patent published in 200981 claims that a biphasic reactionwith dioxane as extraction solvent decreases the process time.The reactive aqueous solution uses sulfuric acid as catalyst andfructose as substrate.

4.1.3 Heterogeneous catalysis – gas–liquid. The CO2–watersystem can replace conventional acids such as HCl and H2SO4

for the catalysis of some chemical reactions, with the advantageof the solution being able to be neutralized by depressurizationwithout requiring salt disposal.82 The main reason that it worksis that CO2 in aqueous solution can generate carbonic acidin situ, which acts as the catalyst for the reaction. There is acorrelation between the pH solution and CO2 pressure, lowerpH values resulting from higher CO2 pressures. The optimum


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 4 Conversion of carbohydrates to HMF catalyzed by mineral or organic acidsa


Entry(ref.) Biomass source Solvent Catalyst Temp. (◦C) Time

Conver-sion (%)

HMFselectivity (%)

Isolation/deter-mination method

182 Inulin H2O 6 MPa CO2 200 45 min 100 53 HPLC283 Fructose (0.05 M) Subcritical H2O — 240 120 s — — HPLC

HCl 240 120 s — 44.7 HPLCH2SO4 240 120 s — 40.3 HPLCH3PO4 240 120 s — 65.3 HPLCCitric acid 240 120 s — 49.3 HPLCMaleicacid

240 120 s — 60.0 HPLC

PTSA 240 120 s — 37.0 HPLCOxalic acid 240 120 s — 17.4 HPLC

383 L-Sorbose (0.05 M) Subcritical H2O H3PO4 240 120 s — 50.0 HPLC483 D-Mannose (0.05 M) Subcritical H2O H3PO4 240 120 s — 31.1 HPLC583 D-Galactose (0.05 M) Subcritical H2O H3PO4 240 120 s — 27.3 HPLC683 D-Glucose (0.05 M) Subcritical H2O H3PO4 240 120 s — 30.0 HPLC783 Sucrose (0.05 M) Subcritical H2O H3PO4 240 120 s — 40.1 HPLC883 Cellobiose (0.05 M) Subcritical H2O H3PO4 240 120 s — 27.2 HPLC984 Fructose Supercritical

acetone–H2O(90:10)

H2SO4 180 (20 MPa) 120 s — 77 HPLC

1084 Glucose Supercriticalacetone–H2O(90:10)

H2SO4 180 (20 MPa) 120 s — 48 HPLC

1184 Sucrose Supercriticalacetone–H2O(90:10)

H2SO4 180 (20 MPa) 120 s — 56 HPLC

1284 Inulin Supercriticalacetone–H2O(90:10)

H2SO4 180 (20 MPa) 120 s — 78 HPLC

a PTSA, p-toluenesulfonic acid.

CO2 pressure was achieved at 6 MPa, resulting in a maximumHMF yield for a variety of temperatures, which indicates that anoptimum reaction pH is obtained with this pressure. Also, theeffects of temperature, time reaction and initial concentrationof inulin on the HMF yield were studied by Han et al.82 Similarbehaviour was observed when these conditions were varied: theHMF yield increased until it reached a maximum value, afterwhich it started decreasing. This was explained by the highreactivity of HMF, which results in the formation of by-products.Optimal conditions were obtained with a CO2 pressure of 6 MPaat 200 ◦C and a reaction time of 0.75 h, which led to a 53% yieldof HMF (Table 4, entry 1).

4.1.4 Subcritical or supercritical solvents. Without catalyst,using a temperature in the range 473–593 K, and a residencetime up to 900 s, many compounds were produced (furfural,humin, soluble polymers, aldehydes, ketones, monosaccharidesand organic acids, Scheme 6) during production of HMF fromfructose in subcritical water.83 With increasing temperature, theamount of by-products increased, especially formic and lacticacids. The amount of HMF produced increased until 530 K,decreasing for higher temperatures with significant productionof formic, lactic and acetic acids. The reaction time favouredHMF production until approximately 200 s, and after this timethe HMF was slowly converted to the organic acids. Asghariet al.83 have also reported that at lower pH the rehydration ofHMF to levulinic and formic acids occurs, whereas for higher

Scheme 6 83.

pH the formation of soluble polymers is favoured. In this study,hydrochloric, sulfuric, phosphoric, oxalic, citric, maleic, and p-toluenesulfonic acids were tested as catalysts for the dehydrationof fructose in subcritical water (Table 4, entry 2). Phosphoric acidwas the best catalyst used at lower pH and the best conditionwas achieved at pH = 2 (HMF yield = 65.3%), but at higherpH HCl was the best (33.4% HMF yield at pH 3.0); however,pH = 2 was shown to lead to the best result. Under subcriticalwater conditions, the HMF yield was shown to decrease with theinitial amount of fructose. Low fructose concentrations (0.05 M)were used, and several other mono- and di-saccharides were alsotested (Table 4, entries 3–8).

Different parameters, such as temperature, pressure andreaction time, were studied by Bicker et al.84 for the fructosedehydration reaction in a supercritical acetone–water mixture,


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


and with sulfuric acid as catalyst. Fructose is a carbohydrate withlow solubility in acetone and therefore, water was added to thesystem to enhance the fructose concentration. A similar systembut in subcritical water83 gave a lower HMF selectivity, especiallywith glucose and sucrose as substrates (Table 4, entries 9–12vs. 2, 6, 7). There were no solids (humins) produced, althoughother by-products such as furfural, glucose, methylglyoxal,dihydroxyacetone and levulinic acid were formed, but with ayield lower than 6%. Years later, this group reported85 thestudy of the same reaction conducted in sub- and supercriticalmethanol and subcritical acetic acid, obtaining furfural-ether(5-methoxymethylfurfural with 79% selectivity and 99% con-version) and furfural-ester (5-acetoxymethylfurfural with 38%selectivity and 98% conversion).

4.1.5 Heterogeneous catalysis – solid–liquid.

Ion exchange resins. Vinke et al.86 reported fructose dehydra-tion using a dehydration set-up consisting of a column with anion exchange resin as catalyst and a separate loop for adsorptionof HMF onto the activated carbon, to avoid the formation ofside-products. Therefore, the HMF is selectively adsorbed in thecarbon during the reaction, and then is extracted with organicsolvents. Thus, the HMF recovery is influenced by the presenceof catalytic sites on the carbon and the pH of the extractingsolution. Although the reaction temperature was not so high,the reaction time was 48 h, but still 77% HMF selectivity couldbe achieved with this system (Table 5, entry 1).

Improvement of HMF selectivity has been achieved bycarrying out fructose dehydration in organic solvents insteadof aqueous solutions, DMSO being the solvent selected for thistransformation.65a,65c,87 Halliday et al.87b reported the one-potsynthesis of 2,5-diformylfuran (DFF), via fructose dehydrationto HMF. The authors claimed that they tried to reproduceseveral reported methods for HMF synthesis, and they did notobtain the expected yields. Consequently, they reported HMFsynthesis with an ion-exchange resin in DMSO, for 5–25 h, at100 ◦C, with high HMF selectivity (Table 5, entries 2 and 3).

In 2009 Shimizu et al.88 reported fructose dehydration inDMSO and tested several heterogeneous catalysts (heteropolyacid, zeolite and acidic resin). In order to extract the waterformed during the reaction, a mild evacuation method wasdeveloped by performing the reaction under vacuum (0.97 ¥105 Pa). Thereby not only the fructose conversion was improvedto 100%, but also the HMF yield was increased to 97%(FePW12O40 Table 5, entry 8). The authors proved that this mildevacuation method gives better results than using molecularsieves as water evacuation agents (Table 5, entries 8, 9 and 10).Another extraordinary result was achieved when the Amberlyst15 catalyst was reduced to a powder (0.15–0.053 mm). Forthis situation, complete transformation of fructose into HMFwas observed (100% conversion with 100% selectivity) even at50 wt.% fructose solutions in DMSO (Table 5, entries 6 and7). This result was achieved even without water evacuation. Theauthors proposed that reduction of the particle size enhances theremoval of adsorbed water from the surface and near-surface ofthe catalyst.88 This result appears to be the best one achieved sofar, but unfortunately the presence of DMSO makes isolation ofthe final product difficult.

In 200789 Dumesic et al. reported the fructose dehydration onsolvent systems containing NMP (1-methyl-2-pyrrolidinone) asadditive in the aqueous phase. MIBK (methyl isobutyl ketone)or dichloromethane were used as extraction solvents. Differentsubstrates, such as fructose, inulin and sucrose were studied usingan ion exchange resin as catalyst. For inulin, the dehydrationreaction was complete with an HMF selectivity of 69% (Table 5,entry 13). Using sucrose as starting material under the samereaction conditions (Table 5, entry 15), only the monomerfructose reacted, providing a conversion of 60%, with an HMFselectivity of 74%. The dehydration reaction occurred even inthe absence of the resin catalyst, with similar HMF selectivity,although the presence of the catalyst allowed a decrease intemperature from 120 to 90 ◦C. The authors studied the DMSOcontent in the aqueous phase, and concluded that the increaseof the amount of DMSO also increased the HMF selectivity.However, for higher amounts of DMSO the carry-over to theorganic phase increased, complicating the HMF separationprocedure. The same behaviour was observed when NMPwas used as additive in the aqueous phase. Dichloromethane(DCM) was tested as extraction solvent (Table 5, entries 12,14 and 16), providing good reaction rates and selectivity.However the DMSO carry-over in DCM is much higher thanfor MIBK, complicating once again the HMF separationprocedure.

It has been reported that organic solvents such as DMSO canimprove fructose dehydration, avoiding the formation of by-products65a,87b such as levulinic acid and humins from HMF, butthis solvent has the disadvantage of difficult separation from thefinal product. To overcome this problem, an acetone–DMSO(7:3) solvent system in the presence of a strong acid cation-exchange resin catalyst was used , with microwave irradiationas the heating source.65c The authors claimed that the use ofacetone is beneficial due to the its low boiling point, which makesseparation of the final product easier. Due to the low solubilityof fructose in acetone, DMSO was used as co-solvent. Twodifferent fructose concentrations were tested, and for the samereaction conditions the HMF selectivity for the higher fructoseconcentration decreased, although not significantly (Table 5,entries 17 and 18). It was possible to recycle the catalyst for atleast 5 cycles without loss of selectivity or efficiency.

In 2008, Watanabe and co-workers reported fructose dehy-dration starting from different substrate concentrations.90 Theystarted the study by heating an aqueous solution of fructosewith a microwave irradiation (150 ◦C) with a resin as catalyst,and although they obtained a good conversion (82.6%), theHMF selectivity was very low (Table 5, entry 19). To attain abetter yield, acetone was chosen as co-solvent, since it has a lowboiling point (56 ◦C), and fructose has been shown to rearrangeto the furanoid form in acetone–water mixtures, favouringHMF formation.90 Using the same reaction conditions, a slightdecrease of HMF selectivity was obtained for an increasedamount of fructose (Table 5, entries 20–23). When the samereaction was heated in a sand bath, the fructose conversion andHMF yield decreased to 22.1% and 13.7%, respectively, whilethe corresponding value for microwave heating was 91.7% and70.3%, respectively (Table 5, entry 20). It was possible to recyclethe catalyst for at least 5 cycles without the lost of selectivity orefficiency.


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 5 Conversion of carbohydrates to HMF under heterogeneous conditionsa


Entry(ref.)


Temp.(◦C) Time

Conver-sion (%)


Isolation/determinationmethod

Catalyst,reactionmediumreuse

186 Fructose H2O Ion-exchangeresin/activatedcarbon

90 48 h — 77 HPLC —

287b Fructose DMSO Dowex-typeion-exchangeresin

110 5 h 100 85 GC–MS —

387b Fructose DMSO Dowex-typeion-exchangeresin

80 25.5 h 100 77 GC–MS —

488 Fructose DMSO Amberlyst 15pellets withevacuation(0.97 ¥ 105 Pa)

120 2 h 100 92 HPLC —

588 Fructose DMSO Amberlyst 15Pellets (0.71–0.5 mm)

120 2 h 100 76 HPLC —

688 Fructose DMSO Amberlyst 15Powder(0.15–0.053 mm)

120 2 h 100 100 HPLC —


DMSO Amberlyst 15Powder(0.15–0.053 mm)

120 2 h 100 100 HPLC —

888 Fructose DMSO FePW12O40 withevacuation(0.97 ¥ 105 Pa)

120 2 h 100 97 HPLC —

988 Fructose DMSO FePW12O40 120 2 h 100 49 HPLC —1088 Fructose DMSO FePW12O40 with

evacuation (4 Asieves )

120 2 h 100 69 HPLC —


4:6 H2O–NMP /MIBK

Ion exchangeresin (Diaion R©)

90 18 h 98 85 MIBKextraction

—


5:5 H2O–DMSO /DCM

— 120 5.5 h 92 80 DCMextraction

—

1389 Inulin(10 wt.%)

4:6 H2O–NMP /MIBK


90 21 h 100 69 MIBKextraction

—

1489 Inulin(10 wt.%)

5:5 H2O–DMSO /DCM

— 120 6.5 h 100 61 DCMextraction

—

1589 Sucrose(10 wt.%)

5:5 H2O–NMP /MIBK


90 21 h 58 74a MIBKextraction

—

1689 Sucrose(10 wt.%)

5:5 H2O–DMSO /DCM

— 120 6.5 h 60 69a DCMextraction

—

1765c Fructose(2 wt.%)

Acetone–DMSO(7:3)

Dowex-typeion-exchangeresin

150 (MW) 5 min20 min

88.299.0

89.688.3

HPLC Ionexchangeresinrecycledfor 5cycles

1865c Fructose(10 wt.%)

Acetone–DMSO(7:3)


150 (MW) 20 min30 min

99.099.4

84.182.1

HPLC —


H2O Dowex-typeion-exchangeresin

150 60 min 82.6 34 HPLC —


Acetone–H2O(70:30 w/w)


150 (MW) 10 min 91.7 70.3 HPLC Catalystsrecycledfor atleast 5cycles




150 (MW) 10 min 98.6 66.6 HPLC —




150 (MW) 10 min 99.6 52.7 HPLC —


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 5 (Contd.)


Entry(ref.)


Temp.(◦C) Time

Conver-sion (%)



Catalyst,reactionmediumreuse



Dowex-typeion-exchange resin

150(MW)

10 min 98.1 51.5 HPLC —



Dowex-typeion-exchange resin

150 10 min 22.1 13.7 HPLC —

2573b Fructose(20 wt.%)

[BMIM][Cl] Amberlyst 15 80 10 min 98.6 83.3 HPLC Catalyst/solventrecycling for atleast 7 cycles

2673b Fructose(20 wt.%)

[BMIM][Cl] Amberlyst 15 120 1 min 99.3 82.2 HPLC —

2773a Fructose(20 wt.%)

[BMIM][Cl]–acetone

Amberlyst 15 25(RT)

6 h 90.3 86.5 HPLC —

2887a Fructose [BMIM][BF4]–DMSO (5:3)

Amberlyst 15 80 32 h — 87 HPLC/UV —

2987a Fructose [BMIM][BF4]–DMSO (5:3)

PTSA 80 32 h — 68 HPLC/UV —

3087a Fructose [BMIM][PF6]–DMSO (5:3)

Amberlyst 15 80 24 h — 80 HPLC/UV —

3187a Fructose [BMIM][PF6]–DMSO (5:3)

PTSA 80 20 h — 75 HPLC/UV —

3287a Fructose [BMIM][BF4] Amberlyst 15 80 3 h — 52 HPLC/UV —3366 Fructose DMF HT/Amberlyst 15 100 3 h 99 76 HPLC —3466 Glucose DMF Amberlyst 15 100 3 h 69 0 HPLC —3566 Glucose DMF HT/Amberlyst 15 80 9 h 73 58 HPLC Catalysts

recycled for atleast 3 cycles

3666 Sucrose DMF HT/Amberlyst 15 120 3 h 58 93 HPLC —3766 Cellobiose DMF HT/Amberlyst 15 120 3 h 52 67 HPLC —3859 Fructose H2O–MIBK (1:5) Dealuminated

H-form mordenites165 2 93 73 MIBK

extraction/HPLC—

3961d Glucose [EMIM][Cl] H2SO4 120 3 h 93 66 EtOAc extraction —4061d Glucose [EMIM][Cl] CF3SO3H 120 3 h 87 46 EtOAc extraction —4161d Glucose [EMIM][Cl] HNO3 120 3 h 56 77 EtOAc extraction —4261d Glucose [EMIM][Cl] CF3COOH 120 3 h 58 75 EtOAc extraction —4361d Glucose [EMIM][Cl] HCl 120 3 h 53 62 EtOAc extraction —4461d Glucose [EMIM][Cl] CH3SO3H 120 3 h 73 58 EtOAc extraction —4561d Glucose [EMIM][Cl] H3PO4 120 3 h 17 95 EtOAc extraction —4661d Glucose [EMIM][Cl] 12-TPA 120 3 h 82 81 EtOAc extraction —4761d Glucose [EMIM][Cl] 12-MPA 120 3 h 71 89 EtOAc extraction —4861d Glucose [EMIM][Cl] 12-TSA 120 3 h 69 82 EtOAc extraction —4961d Glucose [BMIM][Cl] 12-MPA 120 3 h 71 89 EtOAc extraction —5061d Glucose [BDMIM][Cl] 12-MPA 120 3 h 57 88 EtOAc extraction —5161d Glucose [BMPy][Cl] 12-MPA 120 3 h 52 87 EtOAc extraction —5261d Glucose [EMIM][Cl]–

acetonitrile12-MPA 120 3 h 99 98 EtOAc extraction —

5361d Glucose [BMIM][Cl]–acetonitrile

12-MPA 120 3 h 99 98 EtOAc extraction —

a HMF selectivity is based on fructose content. [BMIM][Cl], 1-ethyl-3-methylimidazolium chloride; [BMIM][BF4], 1-butyl 3-methyl imidazoliumtetrafluoroborate; [BMIM][PF6], 1-butyl 3-methyl imidazolium hexafluorophosphate; DMSO, dimethyl sulfoxide; DMF, dimethylformamide,NMP, 1-methyl-2-pyrrolidinone; MIBK, methyl isobutyl ketone; DCM, dichloromethane; HT, Mg–Al hydrotalcite; TPA, 12-tungstophosphoricacid (H3PW12O40); MPA, 12-molybdophosphoric acid (H3PMo12O40); TSA, 12-tungstosilicic acid (H3SiW12O40); MSA, 12-molybdosilicic acid(H3SiMo12O40); [BDMIM][Cl], 1-butyl-2,3-dimethylimidazolium chloride; [BMPy][Cl], 1-butyl-3-methylpyridinium chloride; [EMIM][Cl], 1-ethyl-3-methylimidazolium chloride.

A dehydration of fructose using the ionic liquid [BMIM][Cl]with the sulfonic ion-exchange resin, Amberlyst 15, as catalystwas developed by Qi et al.73b Several mineral and Lewis acids,and solid acid anion-exchange resins were tested, the bestcatalyst being Amberlyst 15. This catalytic system resulted in a98.6% fructose conversion with a selectivity of 83.3% for HMFat 80 ◦C and a reaction time of 10 min (Table 5, entries 25 and26). The water content of the ionic liquid was also taken into

account, and for water contents above 5 wt.% the conversionyield and HMF selectivity decreased. Although there were noproducts of HMF self-polymerization, other by-products werefound by HPLC, such as glucose, levulinic acid and formic acid,but in very low yields. The authors tested the HMF stabilityin this catalytic system by adding an HMF sample under thesame reaction conditions, recovering 99.8% after the reactiontime. The HMF was extracted with ethyl acetate, and therefore


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


the ionic liquid and the catalyst could be recycled for at least 7cycles.73b

The same authors73a reported the conversion of fructose intoHMF, again with Amberlyst 15 as catalyst and using [BMIM][Cl]as the solvent, but at room temperature (Table 5, entry 27). Theviscosity of [BMIM][Cl] at room temperature is high, so it wasnot possible to stir the reaction solution without the addition ofa co-solvent. Small amounts of different co-solvents were addedto the reaction mixture, such as DMSO, methanol, ethanol,ethyl acetate, supercritical carbon dioxide, and acetone, the latterbeing the most efficient. The conversion and HMF yield wereabove 80%, independent of the organic solvent used. To improvethe reaction efficiency, fructose had to be pre-dissolved in theionic liquid in a water bath at 80 ◦C for 20 min. The time forreaction was higher than in the previous work73b (6 h vs. 10 min)but this method has the advantage of being performed at roomtemperature. By-products were also formed, but in yields lowerthan 2%.73a

Two ionic liquids, one hydrophobic and one hy-drophilic (1-butyl-3-methyl imidazolium hexafluorophosphate[BMIM][PF6], and 1-butyl-3-methylimidazolium tetrafluorob-orate [BMIM][BF4]), were tested as solvents for fructose de-hydration with Amberlyst 15 or PTSA as catalysts.87a Theaddition of DMSO as co-solvent increased the HMF selectivity,mainly due to an increase on fructose solubility. The fructosedehydration reaction in [BMIM][Cl],73a at the same temperature,was much faster and more selective than when performed with[BMIM][BF4]87a (Table 5, entries 25 vs. 32). This may be dueto fructose solubility differences between [BMIM][BF4] and[BMIM][Cl]. The addition of DMSO to [BMIM][BF4] increasedthe HMF yield to a higher value than obtained with [BMIM][Cl](Table 5, entries 28 vs. 25).

The ‘site isolation’ concept of supported reagents allows thesimultaneous use of otherwise incompatible reactive function-alities, such acid/base pairs. Takagaki et al.66 reported glucosedehydration to HMF catalyzed by a solid acid/base catalystvia one-pot reaction under mild conditions. The base catalystis necessary for isomerisation of glucose to fructose, and theacidic catalyst will catalyze the dehydration reaction (Scheme 7).Firstly, two individual reactions were screened to identify thebest solid catalyst for both reactions. The best base catalystfor the glucose isomerisation was Mg–Al hydrotalcite (HT),consisting of layered clays with HCO3 groups on the surface.For the fructose dehydration Amberlyst 15 was chosen as theacid catalyst. The combination of these two solid catalystsimproved the glucose transformation from zero selectivity to76% (Table 5, entries 34 vs. 33), improving the conversionas well. Other substrates were tested also with high HMFyields (Scheme 7, Table 5, entries 36 and 37). The reactionsolvent was DMF (N,N-dimethylformamide), but others, suchas DMSO and acetonitrile, were also tested with good results.However, it is important to highlight again that the use of DMSOmakes HMF separation difficult, and is not ideal for industrialproduction.

Other solid catalysis. Dehydration of fructose to HMF wasstudied in a batch mode in the presence of dealuminated H-form mordenites as catalysts, at 165 ◦C, and in a solvent mixtureconsisting of water and methyl isobutyl ketone (1:5 by volume).59

The HMF selectivity was optimized testing H-mordenite with

Scheme 7 66.

different Si/Al ratios. The selectivity decreased when increasingthe Si/Al ratio, i.e. by increasing the acidic properties of thecatalysts. The optimum Si/Al ratio achieved was l : 1, and thehigh selectivity obtained (Table 5, entry 38) was correlatedwith the shape selectivity properties of H-mordenites (bidimen-sional structure), and particularly with the absence of cavitieswithin the structure allowing further formation of secondaryproducts.

Several liquid (H2SO4, CF3SO3H, CH3SO3H, CF3COOH,HNO3, HCl and H3PO4) and solid acids, [12-tungstophosphoricacid (12-TPA (H3PW12O40)), 12-molybdophosphoric acid(12-MPA (H3PMo12O40)), 12-tungstosilicic acid (12-TSA(H3SiW12O40)), and 12-molybdosilicic acid (12-MSA(H3SiMo12O40))] were tested as catalysts for the glucosedehydration to HMF, with [EMIM][Cl] as solvent (Table 5,entries 39–53).61d With all of these catalysts, 4 to 20% ofhumins and others by-products were formed. 12-MPA waschosen for further studies due to the best performance andselectivity (Table 5, entry 47, 71% glucose conversion with 89%HMF selectivity). With this catalyst several other ionic liquids,such as [EMIM][Cl] (1-ethyl-3-methylimidazolium chloride),[BDMIM][Cl] (1-butyl-2,3-dimethylimidazolium chloride)and [BMPy][Cl] (1-butyl-3-methylpyridinium chloride) weretested (Table 5, entries 49–51). There was a lower activity of12-MPA in the ionic liquids [BDMIM][Cl] and [BMPy][Cl]than the other two. With [BDMIM][Cl] the lower activity maybe due the acidic proton lost from the imidazolium cation.So the loss of the acidity in the solvent (in this case, the ionicliquid) reduces the glucose conversion and HMF selectivity.The addition of acetonitrile to the ionic liquid as co-solventenhances the glucose conversion up to 99%, with a 98% HMFselectivity, with [BMIM][Cl] or [EMIM][Cl] as solvent, and noformation of humins (Table 5, entries 52 and 53). A glucosedehydration mechanism by 12-MPA was proposed, wherethe authors believed that a key intermediate in the reactionpathway to HMF was a 1,2-enediol. The high selectivity ofheteropoly acids was attributable to stabilization of the reactionintermediates involved in formation of HMF. In the absence ofacetonitrile as a co-solvent, moderate amounts of humins wereformed.61d

4.1.6 Solvents as reaction promoters. In 1987 Musauet al.65a demonstrated that fructose can be converted intoHMF in the presence of DMSO as solvent at 150 ◦C, withno catalyst added (Table 6, entry 1). They tested different


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 6 Conversion of carbohydrates to HMF using solvents as reaction promotersa


Entry(ref.)

Biomasssource Reaction medium Catalyst

Temp.(◦C) Time

Conver-sion (%)


Isolation/determination method

Isolatedyield (%)


165a Fructose DMSO — 150 2 h — 92 EtOAcextraction/silica gelchromatography withDCM

— —

268 Fructose 1-H-3-methylimidazolium chloride

— 90 45 min 100 92 Diethyl ether extraction 86 Solvent/catalystreused for 5 cycles

394 Fructose [ASBI][Tf] / DMSO — 100(MW)

6 min 98 80 HPLC — —

494 Fructose [ASCBI][Tf] / DMSO — 100(MW)

6 min 100 84 HPLC — —

594 Fructose ILIS–SO3H / DMSO — 100(MW)

4 min 100 70.1 HPLC — —

694 Fructose ILIS–SO2C l/ DMSO — 100(MW)

4 min 100 67.2 HPLC — —

761a Fructose Cholinechloride–citric acid

— 80 1 h 91.1 83.8 EtOAc extraction 72.2 Ionic liquidreused for 8 cycles

861a Fructose Cholinechloride–CrCl3

— 80 1 h 92 <20 EtOAc extraction — —

961a Fructose Cholinechloride–ZnCl2

— 80 1 h 25 <7 EtOAc extraction — —

1061c Inulin Cholinechloride–oxalic acid

— 80 2 h 100 56 EtOAc extraction — Ionic liquidreused for 6 cycles

1161c Inulin Cholinechloride–oxalic acid /ethyl acetate

— 80 2 h 100 64 EtOAcextraction/HPLC

— —

1261c Inulin Cholinechloride–citric acid

— 50+80 2+2 h 88 65 EtOAcextraction/HPLC

— —

1395 Fructose Pyridinium chloride — 120 30 min — 70 Silica gelchromatography (ethylacetate–petroleumether)

70 —

1495 Inulin Pyridinium chloride — 120 30 min — 60 — — —1595 Levan Pyridinium chloride — 120 30 min — 60 — — —1695 Glucose Pyridinium chloride — 120 30 min — 5 — — —1795 Sucrose Pyridinium chloride — 120 30 min — 30 Silica gel

chromatography (ethylacetate–petroleumether)

30 —

a [ASBI][Tf], 3-allyl-1-(4-sulfobutyl)imidazolium trifluoromethanesulfonate; [ASCBI][Tf], 3-allyl-1-(4-(sulfurylchloride)butyl)imidazolium trifluo-romethanesulfonate; DMSO, dimethyl sulfoxide; [EMIM][Cl], 1-ethyl-3-methylimidazolium chloride; DCM, dichloromethane; ILIS, ionic liquidimmobilized on silica gel.

fructose/DMSO molar ratios and found that an optimumconversion was attained for a ratio of 0.8. The authors suggestedthat DMSO associates initially with only D-fructose at the startof the dehydration reaction, after which the generated waterassociates with DMSO, reducing the amount of DMSO availableto D-fructose. Consequently, DMSO had to be sufficiently inexcess to associate with all the water released at the end of thereaction.

Amarasekara et al.91 studied the mechanism of the dehy-dration of fructose to HMF in DMSO at 150 ◦C withoutany added mineral or Lewis acid catalyst by monitoring thereaction by NMR spectroscopy (Scheme 8). It was possible toidentify an intermediate (4R,5R)-4-hydroxy-5-hydroxymethyl-4,5-dihydrofuran-2-carbaldehyde using a combination of 1H and13C NMR spectra.

Ionic liquids have been a promising solvent for carbohydratetransformations.92 These solvents can dissolve carbohydrates,even at high concentrations,93 and can be easily recycled.

Scheme 8 91.

Furthermore, they have been shown not only to act as solvents,but also as reaction promoters for carbohydrate dehydrationreactions.68,79


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


In 2006 HMF formation starting from fructose and sucrose,in an ionic liquid used as reaction solvent and reaction pro-moter was reported.68 [HMIM][Cl] (1-H-3-methylimidazoliumchloride) is a protic ionic liquid that could convert completelyfructose with 92% HMF selectivity (Table 6, entry 2). Theinfluence of the ionic liquid as both solvent and catalystis more important for the formation of HMF than for itsdecomposition. Kinetic studies showed that the energies ofactivation for the formation and decomposition of HMF aresimilar to those reported for the reaction catalyzed by solidcatalysts.68 The dehydration reaction was also tested with sucroseas starting material, and a rapid cleavage of sucrose into glucoseand fructose was observed, but as reported before for otherconditions,7e the glucose moiety did not react, although thefructose conversion was complete. After HMF extraction withdiethyl ether, it was possible to recycle the ionic liquid at least 5times.

The use of ionic liquids as solvents and reaction pro-moters was also reported by Yokoyama et al.94 In thiswork microwave irradiation was used to heat the fruc-tose dehydration reaction in a Lewis acidic ionic liquid,[ASCBI][OTf] (3-allyl-1-(4-(sulfurylchloride)butyl)imidazoliumtrifluoromethanesulfonate), and a Brønsted-acidic ionic liq-uid [ASBI][OTf] (3-allyl-1-(4-sulfobutyl)imidazolium trifluo-romethanesulfonate) and their silica gel immobilized coun-terparts (Scheme 9).94 The two ionic liquids with DMSO asco-solvent, converted fructose in very good yields, and goodselectivity for HMF (Table 6, entries 3 and 4). The Lewis acidicionic liquid was a better reaction medium than the Brønstedacidic ionic liquid. These ionic liquids, when immobilizedon silica, converted fructose with 100% conversion, but withmedium selectivity for HMF (Table 6, entries 5 and 6).

Scheme 9 94.

Several ionic liquids and pyridinium salts were tested, in-cluding Brønsted-acidic ionic liquids, Lewis-acidic solvents(e.g. ChoCl–metal chlorides), basic solvents (e.g. ChoCl–urea,1,1,3,3-tetramethylguanidinium trifluoroacetate and lactate)and choline chloride (ChoCl)-based deep eutectic mixtures.Without adding any catalyst, these solvents were tested for theconversion of fructose to HMF at 80 ◦C for 1 h.61a The Lewisacids ZnCl2 and CrCl3 in ChoCl–metal chloride produced lessthan 20% of HMF (Table 6, entries 8 and 9). The most efficientsolvent–catalyst tested was choline chloride–citric acid, whichled to 91.1% conversion with 83.8% HMF selectivity (Table 6,entry 7). Ethyl acetate was reported as extraction solvent andshowed good efficiency. Due to the immiscibility with the ionic

liquid–acid mixture reactive phase, the product formed wasextracted without any cross-contamination (Fig. 2). This ionicliquid system has the advantage of being biodegradable andnon-toxic.61a

Fig. 2

Recently the same authors reported61c one-pot inulin hydrol-ysis and fructose dehydration with moderate HMF selectivity(Table 6, entries 10–12) in choline-based ionic liquids at 80 ◦C.The acidic CholCl–oxalic acid and CholCl–citric acid ionicliquid acted as solvent and catalyst, and it was possible torecycle the CholCl–oxalic acid system for at least six cycles,just by extracting the product with ethyl acetate. A biphasicreaction system with ethyl acetate as extraction solvent providedan improved HMF selectivity (Table 6, entry 11).

Fayet et al. reported in 198395 HMF synthesis from fructose,glucose, sucrose, inulin, and levan (fructose polymer). Differentpyridinium salts were tested as promoters for HMF synthesis.For fructose, inulin and levan, a moderate HMF yield wasachieved with pyridinium chloride, at 120 ◦C for 30 min (Table 6,entries 13, 14 and 15). The same did not occur for glucose orsucrose, for which the HMF yield was very low (Table 6, entries16 and 17).

A patent was published in 200896 in which the authors claimedthat, by heating a carbohydrate in an ionic liquid, and usingextraction solvents, it was possible to obtain pure HMF.

4.2 Metal catalysis

4.2.1 Chromium-based catalysts. Zhang et al. reported79

the synthesis of HMF starting from fructose or glucose with verygood selectivity. They studied the effect of different ionic liquidsin the fructose dehydration. After choosing [EMIM][Cl] (1-ethyl-3-methylimidazolium chloride) as solvent, they tested differentcatalysts, such as several metal chlorides, and mineral and Lewisacids. In the absence of catalyst and at 120 ◦C, they obtaineda fructose conversion of almost 100%, with approximately 70%selectivity (Table 7, entry 1). This system was not so efficient forglucose, since even with an increase of the temperature to 180 ◦Conly 40% conversion was obtained, with less than 5% selectivity(Table 7, entry 2). However glucose conversion increased to near70%, and the selectivity was approximately 90% when a catalyticamount of chromium(II) chloride was added (Table 7, entry 3).The authors proposed that the catalyst [EMIM][Cl]/CrCl2 wasinducing glucose isomerisation to fructose and then, fructosewas rapidly converted to HMF (Scheme 10).79 The HMFstability was studied by heating pure HMF at 100 ◦C for 3 h in[EMIM][Cl] in the presence of a catalytic amount of CrCl2 andas a result, 98% of the HMF was recovered. When no CrCl2 was


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Scheme 10 79.

added to the system, only 28% of the initial HMF was recovered.Similar studies were done with other metal halides with highHMF recovery: CuCl2, VCl4, and H2SO4 with 85, 86 and 98%recovery, respectively. It may be assumed that a catalytic amountof some metal chlorides can not only catalyze the dehydrationreaction, but also stabilize the final product. This may be one ofthe main reasons for not observing polymeric by-products, andonly a negligible amount of levulinic acid being formed. Thismethod was published in 2008 in a patent.97

Using [BMIM][Cl] (1-butyl-3-methylimidazolium chloride)as solvent (100 ◦C, 6 h), several NHC/metal (N-heterocycliccarbene ligand) complexes were tested as catalysts for thedehydration of fructose and glucose (Scheme 11).98 The authorsconcluded that bulky NHC ligands protect the Cr center fromreacting with [BMIM][Cl] and form a sterically crowded metalcenter, therefore providing a higher catalytic efficiency. A goodHMF selectivity was achieved, using these NHC/Cr complexesas catalysts, 96% and 81% for fructose and glucose respectively(Table 7, entries 7 and 5). The HMF yield was confirmed byGC, but it was possible to separate the HMF product fromthe reaction medium by a simple ether extraction. After that,the catalyst and the ionic liquid could be recycled for at leastthree cycles, with some loss of selectivity being observed whenglucose was used as substrate. A higher fructose and glucoseconcentration was tested (20 wt.%) and no decrease of selectivitywas observed (Table 7, entries 6 and 8).

Scheme 11 98.

HMF conversion using [EMIM][HSO4] and [BMIM][Cl] withdifferent substrates, with or without extraction solvents (tolueneor MIBK) was studied.60a [EMIM][HSO4] with toluene or MIBKas extraction solvents completely converted fructose in 79 and88% HMF yield, respectively (Table 7, entry 9 and 10). Thissystem was not so efficient with glucose, and therefore, theauthors changed the ionic liquid to [BMIM][Cl] with CrCl3

as catalyst. This catalyst was chosen instead of CrCl2, since

it is more stable and easily handled under air, much cheaperand it is very likely that Cr2+ is oxidized to Cr3+ in the ILsystem containing dissolved air and water.60a The system with[BMIM][Cl]/CrCl3 without an extraction solvent resulted in a81% HMF yield, which was improved when toluene was addedto the reaction system as an extraction solvent (Table 7, entry 11vs. 13). This result is comparable with the reported99 glucosedehydration in [BMIM][Cl]/CrCl3 with microwave irradiationas a heating source, for only one minute, for which the isolatedHMF yield was 91% (Table 7, entry 18). Other substrates weretested, such as inulin, sucrose, and cellobiose (Table 7, entries14, 15 and 16, respectively), and cellulose (Table 7, entry 17).Although high HMF selectivity was achieved for inulin andsucrose, the same did not happen with cellobiose or cellulose,even when adding H2SO4 into the reaction system for cellulose.

In 2009, Li et al.99 reported the transformation of glucose andcellulose in [BMIM][Cl] (1-butyl-3-methylimidazolium chloride)with CrCl3 as catalyst, affording HMF yields of 91 and 61%,respectively when subjected to microwave irradiation of 400 Wfor only one and two minutes, respectively (Table 7, entries 18and 19). Different cellulose samples were tested reaching 53–62%HMF yields, indicating that this method is affected neither bythe cellulose type nor the polymerization degree. The high yieldsobtained from cellulose are explained by the complete cellulosedissolution in the ionic liquids, leaving cellulose chains accessibleto chemical transformations, and also because [BMIM][Cl] hasexcellent dielectric properties for transformation microwavesinto heat. Although Zhang et al.79 reported smaller HMF yieldsfor glucose transformation with CrCl3 (Table 7, entry 4 vs. 18) in[EMIM][Cl], the authors believe that the microwave irradiationcan improve the catalyst behaviour. The mechanism for thistransformation still remains unknown, although the authorspursued a pathway to glucose isomerisation to fructose.

An extension of this work was made recently by the sameauthors, where they have tested this microwave-assisted trans-formation with other biomass resources, such as corn stalk, ricestraw and pine wood.100 In this work CrCl3·6H2O was used ascatalyst in [BMIM][Cl], for 2–3 min under 400 W microwaveirradiation. HMF yield improvement when using microwaveheating was again confirmed (Table 7, entry 23 vs. 24). Thisreaction was also tested with [BMIM][Br] with similar results,as with [BMIM][Cl] (Table 7, entries 24 vs. 25). [BMIM][Br] canalso dissolve lignocellulosic biomass, and the authors reportedthat the reaction medium has little effect on the dehydrationefficiency as long as the solvent dissolves lignocellulosic biomass.

Chen et al.64 studied the cellulose conversion into HMF usinga ionic liquid–water mixture with CrCl2 as catalyst. At 120 ◦C,with 10 mol% of CrCl2 in [EMIM][Cl] (no water added) 89%HMF conversion was observed (Table 7, entry 26). This highHMF yield implies that not only glucose was converted to HMF,but also other reducing sugars present after cellulose hydrolysis.To enhance the cellulose hydrolysis and dehydration, water wasadded to this catalytic system, but this resulted in a decrease inthe HMF yield, even at higher temperatures (Table 7, entry 24vs. 28).

Recently Zhang et al.101 studied cellulose transformation toHMF in the ionic liquid [EMIM][Cl] using a pair of two metalcatalysts, CrCl2 and CuCl2, with a HMF yield of 55.4% (Table 7,entry 29). In this work a study was carried out to achieve the


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 7 Conversion of carbohydrates to HMF by chromium-based catalystsa


Entry(ref.)


Temp.(◦C) Time

Conver-sion (%)



Isolatedyield (%)



[EMIM][Cl] — 120 3 h 100 70 HPLC — —

279 Glucose(10 wt.%)

[EMIM][Cl] — 180 3 h 40 <5 HPLC — —


[EMIM][Cl] CrCl2 100 3 h 70 90 HPLC — —


[EMIM][Cl] CrCl2 100 3 h 43 70 HPLC — —


[BMIM][Cl] NHC–CrCl2 100 6 h — 81 Diethyl etherextraction/GC

— Catalyst/solventrecycling for atleast 3 cycles


[BMIM][Cl] NHC–CrCl2 100 6 h — 80 GC — —


[BMIM][Cl] NHC–CrCl2 100 6 h — 96 Diethyl etherextraction/GC

— Catalyst/solventrecycling for atleast 3 cycles


[BMIM][Cl] NHC–CrCl2 100 6 h — 96 GC — —

960a Fructose [EMIM][HSO4]/ toluene

— 100 30 min 100 79 Tolueneextraction/HPLC

— —

1060a Fructose [EMIM][HSO4] /MIBK

— 100 30 min 100 88 MIBKextraction/HPLC

— —

1160a Glucose [BMIM][Cl] /toluene

CrCl3 100 4 h 91 91 HPLC — —

1260a Glucose [BMIM][Cl] /MIBK

CrCl3 100 4 h 79 79 MIBKextraction/HPLC

— —

1360a Glucose [BMIM][Cl] CrCl3 100 4 h 83 81 HPLC — —1460a Inulin [EMIM][HSO4] /

MIBK— 100 30 min — 73 MIBK

extraction/HPLC— —

1560a Sucrose [BMIM][Cl] /MIBK

CrCl3 100 4 h — 73 MIBKextraction/HPLC

— —

1660a Cellobiose [BMIM][Cl] /MIBK

CrCl3 100 4 h — 37 MIBKextraction/HPLC

— —

1760a Cellulose [BMIM][Cl] /MIBK

CrCl3–H2SO4

100 4 h — 9 MIBKextraction/HPLC

— —

1899 Glucose [BMIM][Cl] CrCl3 ~200(MW400 W)

1 min — 91 Silica gelchromatography(ethylacetate–petroleumether)

91 —

1999 Cellulose [BMIM][Cl] CrCl3 ~200(MW400 W)

1 min — 61 Silica gelchromatography(ethylacetate–petroleumether)

61 —

20100 Cellulose [BMIM][Cl] CrCl3 ~200(MW400 W)

2.5 min — 62 HPLC

21100 Cornstalk

[BMIM][Cl] CrCl3 ~200(MW400 W)

3 min — 45 HPLC

22100 Ricestraw


3 min — 47 HPLC

23100 Pinewood


3 min — 52 HPLC

24100 Pinewood

[BMIM][Cl] CrCl3 100 (oilbath)

60 min — 6.4 HPLC

25100 Pinewood

[BMIM][Br] CrCl3 ~200(MW400 W)

3 min — 44 HPLC

2664 Cellulose [EMIM][Cl] CrCl2 120 6 h — 89 Acetoneextraction/HPLC


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 7 (Contd.)


Entry(ref.)


Temp.(◦C) Time

Conver-sion (%)



Isolatedyield (%)


2764 Cellulose [EMIM][Cl]–H2O

CrCl2 120 12 h — 13 Acetoneextraction/HPLC

2864 Cellulose [EMIM][Cl]–H2O

CrCl2 140 2 h — 40 Acetoneextraction/HPLC

29101 Cellulose(10 wt.%)

[EMIM][Cl] CrCl2–CuCl2

120 8 h — 57.5 HPLC

30102 Sucrose(20% w/v)

[OMIM][Cl] HCl–CrCl2 120 30 min — 82.0 HPLC






DMA–LiCl H2SO4 100 5 h — 63 HPLC — —


DMA–[EMIM][Cl]

H2SO4 100 2 h — 84 HPLC — —


DMA–LiF H2SO4 80 2 h — 0 HPLC — —


DMA–LiBr H2SO4 100 4 h — 92 HPLC — —NaBr 2 h 93LiI 6 h 89NaI 5 h 91


DMA–LiCl CrCl2 100 5 h — 60 HPLC — —


DMA–LiCl–[EMIM][Cl]

CrCl2 100 6 h — 62 HPLC — —


DMA–LiI CrCl2 100 4 h — 54 HPLC — —


DMA–LiBr CrBr2 100 6 h — 80 HPLC — —

41103 Cellulose DMA–LiCl–[EMIM][Cl]

CrCl2–HCl 140 2 h — 54 HPLC — —

42103 Cellulose [EMIM][Cl] CrCl2–HCl 140 1 h — 53 HPLC — —43103 Cellulose DMA–LiI CrCl2–HCl 140 3 h — <1 HPLC — —

LiBr <144103 Corn stover DMA–LiCl–

[EMIM][Cl]CrCl2–HCl 140 2 h — 48 HPLC — —

a MIBK, methyl isobutyl ketone; MW, microwave irradiation; [BMIM][Cl], 1-ethyl-3-methylimidazolium chloride; [EMIM][Cl], 1-ethyl-3-methylimidazolium chloride; [OMIM][Cl], 1-octyl-3-methylimidazolium chloride; NHC, N-heterocyclic carbene ligand; DMA, N,N-dimethylacetamide.

best molar ratio for the two catalysts CrCl2 and CuCl2, and itwas observed that as little as 3 mol% of CrCl2 in the paired metalchlorides was sufficient to activate the CuCl2-dominant catalystin the [EMIM]Cl solvent. The catalyst and the solvent couldbe recycled for three times using MIBK as extraction solvent.A mechanism for this transformation is being studied by theauthors.

Studies on sucrose hydrolysis and further dehydration toHMF were performed by Chung,102 using a different ionic liquid,1-octyl-3-methylimidazolium chloride ([OMIM][Cl]) as solventand two metal chlorides as catalysts (CrCl2 or ZnCl2) in anacidic medium, HCl (Scheme 12). According to the authors,the acidic medium improves the sucrose hydrolysis, and thecatalysts CrCl2 or ZnCl2 catalyze further glucose dehydration.Firstly, the sucrose hydrolysis to glucose and fructose monomerswas studied in [OMIM][Cl] solutions at 120 ◦C. Even withoutaddition of acid, the sucrose hydrolysis occurred in [OMIM][Cl],although with longer reaction times. With the acid addition, thehydrolysis was faster, but it was also possible to see fast fructose

Scheme 12 102.

disappearance, probably due to the strong chemical reactivityfor isomerisation, dehydration, fragmentation or condensationreactions. The authors did not quantify the by-products formed.When the catalyst CrCl2 was added to the system, an HMF yieldimprovement was observed. Depending on HCl and sucroseconcentrations the time for reaction was adjusted (Table 7,entries 30–32). The best HMF achieved was 82% for a sucroseconcentration of 20% with 0.5 M HCl and CrCl2 as catalyst(Table 7, entry 30). A 50% w/v sucrose concentration was


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


also tested, resulting in a decrease of the HMF yield to 53.2%(Table 7, entry 32).

Binder and Raines reported103 the use of authentic ligno-cellulosic biomass as starting material for HMF production,using DMA–LiCl (N,N-dimethylacetamide–lithium chloride)as solvent. They initiated the study with fructose as startingmaterial, with H2SO4 as catalyst and DMA–lithium salts assolvent, and tested several additives, such as [EMIM][Cl] (1-ethyl-3-methylimidazolium chloride) and other ionic liquids.When different lithium salts were tested, it was observed thatfluoride ions were completely ineffective for HMF synthesis(Table 7, entry 35), although bromide and iodide ions, whichtend to be less ion-paired than fluoride and chloride,103 achievedHMF yields up to 92% (Table 7, entry 36). Based on theseand other experimental results, the authors proposed a reactionmechanism involving an oxocarbenium ion that is attackedby the halide ion (Scheme 13). HMF production startingfrom glucose was also tested with CrCl2, CrCl3 or CrBr3 ascatalyst with DMA–LiCl (or other salts such as LiBr, LiI) assolvent (Table 7, entries 37–40). The halide effect was also verypronounced with this substrate. With chloride anions presentin the reaction mixture (CrCl2 as catalyst and DMA–LiClas solvent, Table 7, entry 37) HMF yields up to 60% wereobtained, and they were enhanced to 62% with the additionof [EMIM][Cl] as additive (Table 7, entry 38). Although theaddition of iodide ions to the reaction mixture with CrCl2 ascatalyst did not improve the HMF yields, the same did nothappen with bromide ions, which improved HMF yields up to80% (Table 7, entry 40). Cellulose was also tested as an HMFsource with CrCl2 and HCl as catalysts. Dissolution of purifiedcellulose in a mixture of DMA–LiCl and [EMIM][Cl] andaddition of CrCl2 or CrCl3 produced HMF from cellulose in upto 54% yield within 2 h at 140 ◦C (Table 7, entries 41, 42). Due tocellulose insolubility, neither lithium iodide nor lithium bromideproduced high yields of HMF (Table 7, entry 43). Finally, thesynthesis of HMF from lignocellulosic biomass was studied. A48% HMF yield (based on cellulose content of the biomass)was achieved with this substrate under similar conditions asfor cellulose (Table 7, entry 44). The authors proposed thatthe formation of HMF from cellulose in DMA–LiCl occursvia saccharification followed by isomerisation of the glucosemonomers into fructose and dehydration of fructose to formHMF. It was possible to separate the HMF formed by an ion-exclusion chromatographic separation, where over 75% of HMFwas recovered. Binder and Raines are the authors of a patentthat describes this technology with the aim of 2,5-dimethylfuranmanufacture.104

Scheme 13 103.

In 2009 Pidko et al.105 studied the reactivity of chromium(II)chloride towards selective glucose dehydration in an ionicliquid medium, combining different methods, such kinetic

experiments, in situ X-ray absorption spectroscopy (XAS), anddensity functional theory (DFT) calculations. The key reactionof the catalytic system [EMIM][Cl]–CrCl2, as reported before,79

is the isomerisation of glucose to fructose. In this work theauthors proposed a mechanism based on that suggested forthe enzymes. In this chemical system the highly concentratedand mobile chloride anions from the ionic liquid promotevarious (de)protonation reactions important for the glucoseisomerisation (Scheme 14). In enzymes, such transformationsare catalyzed by basic amino acid residues at the active site. Theunique transient self-organization of Cr2+ dimers to facilitatethe rate-controlling H shift in glucose isomerisation is possibleas a result of the dynamic nature of the Cr complexes and thepresence of moderately basic sites in the ionic liquid.

Scheme 14 105.

4.2.2 Zirconium and titanium catalysts. Watanabe studiedglucose and fructose reactivity in hot compressed water withhomogeneous or heterogeneous acidic (H2SO4 or TiO2) or alkaliadditives (NaOH or ZrO2).106 They observed that isomerisationbetween glucose and fructose is catalyzed by alkali, and fructosedehydration is promoted by acidic conditions. It seems that theequilibrium favours fructose formation in hot compressed waterbecause the rate of isomerisation of fructose into glucose isnegligible compared to that of glucose into fructose. Zirconia(ZrO2) is a base catalyst that promotes the glucose isomerisation.On the other hand, anatase (TiO2) was found to act as an acidcatalyst to promote formation of HMF.

In 2000 zirconium and titanium hydrogenphosphates in the aand g structural arrangements were reported as catalysts forfructose and inulin dehydration to HMF.60e These reactionswere carried out in aqueous media, but even so no appreciablesubsequent rehydration to levulinic and formic acids occurred.Among the investigated catalysts, both surface Brønsted andLewis acid sites were present, and experimental results showedthat both acid sites may be involved in the catalytic process.However, as the Lewis acid site strength increased, a correspond-ing enhancement of HMF yield is obtained. For example, thelower strength of Lewis acid sites present on the external crystalsurface of c-TiP2O7 with respect to those on c-ZrP2O7 decreasedthe performance of c-TiP2O7 catalyst (Table 8, entry 4 vs. 5 or 6).Inulin showed a similar reactivity to that observed for fructose


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 8 Conversion of carbohydrates to HMF catalyzed by Zr and Ti catalystsa


Entry(ref.)


Temp.(◦C) Time

Conversion(%)

HMFselectivity (%)



160e Fructose H2O a-Titaniumphosphate(a -TiP)

100 0.5 h 29.1 98.3 GC —

1 h 33.4 83.52 h 34.1 75.4

260e Fructose H2O g-Titaniumphosphate(g -TiP)

100 0.5 h 36.7 96.1 MIBK extraction/GC Catalyst andsubstratesolution reusedfor 2 cycles

1 h 46.8 88.62 h 56.6 68.7

360e Inulin H2O g-Titaniumphosphate(g -TiP)


1 h 44.3 94.02 h 91.9 70.7

460e Fructose H2O Cubic titaniumpyrophosphate(c-TiP2O7)

100 0.5 h 24.8 98.7 GC —

1 h 29.3 90.2 h 38.7 72.3

560e Fructose H2O Cubiczirconium-pyrophosphate(c-ZrP2O7)


1 h 52.2 86.02 h 52.8 81.4

660e Inulin H2O Cubiczirconium-pyrophosphate(c-ZrP2O7)


1 h 38.9 89.42 h 50.2 72.3


H2O ZrO2 200(MW)

5 min 65.3 30.6 HPLC —


H2O TiO2 200(MW)

5 min 83.6 38.1 HPLC —


H2O ZrO2 200(MW)

5 min 56.7 10.0 HPLC —


H2O TiO2 200(MW)

5 min 63.8 18.6 HPLC —


H2O SO42-–ZrO2 200

(MW)5 min 88.7 37.4 HPLC —


Acetone–DMSO (7:3w/w)

SO42-–ZrO2 180

(MW)20min

93.6 72.8 HPLC —

1363 Glucose(7.6 wt.%)

DMSO — 130 4 h 94 4.3 HPLC —


DMSO SO42-–ZrO2 130 4 h 95.2 19.2 Et2O

extraction/HPLC—


DMSO CSZA-3 130 4 h 99.1 48.0 HPLC Catalyst reusedfor at least 5cycles


DMSO CSZA-3 130 4 h 98.1 39.2 HPLC —


DMSO — 130 4 h 99.6 71.9 HPLC —

1863 Fructose(7.6 wt.%)

DMSO SO42-–ZrO2 130 4 h 99.8 67.7 HPLC —

1963 Fructose(7.6 wt.%)

DMSO CSZA-3 130 4 h 99.4 56.6 HPLC —


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 8 (Contd.)


Entry(ref.)


Temp.(◦C) Time

Conversion(%)

HMFselectivity (%)



20109 Cellulose Hot compressedH2O

ZrO2–TiO2 250 5 min 70 13 HPLC —

21109 Glucose Hot compressedH2O

ZrO2–TiO2 250 5 min 80 28 HPLC —

22110 Fructose Subcritical H2O ZrP 240(3.35MPa)

120 s 80.6 61.3 HPLC Reused for 6–7cycles

23110 Glucose Subcritical H2O ZrP 240(3.35MPa)

180 s 53.1 39.0 HPLC Reused for 6–7cycles

a CSZA-3, SO42-/ZrO–Al2O3; DMSO, dimethyl sulfoxide; MIBK, methyl isobutyl ketone; MW, microwave irradiation.

(Table 8, entries 3 and 6). Cubic zirconium pyrophosphate andg-titanium phosphate offered the best performances in terms ofactivity and selectivity (Table 8, entries 5 and 2).

Watanabe et al.107 studied the HMF formation from fructoseand glucose with TiO2 and ZrO2 as catalysts in water and with amicrowave irradiation (200 ◦C) as heating source. The advantageof using these heterogeneous catalysts when compared withhomogeneous catalysts (such as HCl or H2SO4) is the lowcorrosion and easy separation. With the reported method, goodconversion yields were achieved, but selectivity for HMF was low(Table 8, entries 7–10). The zirconium or titanium phosphatescatalysts used by Benvenuti60e had a better performance than theTiO2 and ZrO2 described in this work.

In continuation of the heterogeneous catalysis study, theseauthors reported in 2009108 the behaviour of the solid acidcatalyst sulfated zirconia in the dehydration of fructose to HMF.In this study they also used microwave heating. The catalyst wascharacterized, and in aqueous solutions the HMF selectivity waslow (37.4%, Table 8, entry 11); this may be due to the deactivationof the active acid sites on the catalyst by water. Therefore, asbefore,90 the authors changed the solvent to an acetone–DMSOmixture. The results were very satisfactory, with 93.6% fructoseconversion and 72.8% HMF selectivity being achieved in thepresence of SO4

2-–ZrO2 as catalyst for 20 min at 180 ◦C (Table 8,entry 12). The authors are working on in situ removal of watergenerated in the reaction to avoid catalyst deactivation.

In the same year another group reported63 the glucose dehy-dration with SO4

2-–ZrO2 (CSZ) and SO42-/ZrO–Al2O3 (CSZA-

1–5, depending on the Zr–Al mole ratio) catalysts. CSZA-1–5have acidic and basic active sites, such that increasing the Alratio increased the number of basic sites. When these catalystswere tested for glucose dehydration, the authors expectedthat by increasing the basic sites on the catalyst, the glucoseisomerisation would also be increased, resulting in higher HMFyields. However, this was not observed, and in fact the catalystwith higher acidity and moderate basicity was better for theformation of the target product (Table 8, entries 14 vs. 15).Another important observation is the fact that the acid sites onthe CZA or CSZA catalysts exhibited no catalytic improvementfor the conversion of fructose to HMF when compared with thesame conditions without a catalyst (Table 8, entry 17 vs.18 or

19). The authors suggested that the production of HMF in thissystem may not be mainly via glucose isomerisation–dehydrationprocess. The catalyst CSZA-3 was recycled for at least5 cycles.

With the objective of coupling in one-pot the hydrolysis anddehydration reactions to produce HMF from lignocellulosicbiomasses (i.e. sugarcane bagasse, rice husk and corn cob),conditions employing heterogeneous catalysts TiO2, ZrO2 andmixed-oxide TiO2–ZrO2 under hot compressed water (HCW)were applied.109 It was found that the catalyst preparationprocedure affected its reactivity, and with different Ti/Zrratios and different calcination temperatures the catalyst acid-ity/basicity was different. Although these catalysts resulted ingood conversion (70–80% to glucose and cellulose, Table 8,entries 20 and 21), several other products were formed. TheHMF yield was approximately 28% for glucose and 13% forcellulose.109

Asghari et al.110 reported the fructose and glucose dehydrationreaction with zirconium phosphate as catalyst, in subcriticalwater. The authors claimed that only a few solid catalysts wereacceptable for reactions in aqueous solutions (especially water athigh temperatures and pressure or subcritical water) in terms oftheir activity, stability and insolubility. It was found that zirco-nium phosphates were stable in these conditions. They induceda moderate selectivity in the presence of fructose, comparablewith that obtained with zirconium pyrophosphate,60e but ledto higher conversions (Table 8, entry 22 vs. 6). This catalystwas not the best for conversion of glucose into HMF (Table 8,entry 23).

For this group of catalysts based on zirconium or titaniummetals, although good conversions could be obtained forfructose, the HMF selectivity was low, and several other by-products were formed. For glucose conversion, the obtainedconversion yields were in general moderate, and the HMFselectivity was also low. Thus, despite the advantage of usinga heterogeneous catalysis due to the ease of catalyst recyclingand lower corrosion effects, the catalyst and/or the reactionconditions had to be improved for better HMF selectivity.

4.2.3 Lanthanides as catalysts. Ishida et al.111 shown thatlanthanide ions can catalyse glucose dehydration to HMF. No


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 9 Conversion of glucose to HMF catalyzed by YbCl3a


Entry(ref.)

Biomasssource Solvent Catalyst Temp. (◦C) Time Conversion (%)

HMFselectivity (%)


1112 Glucose [EMIM][Cl] YbCl3 160 1 h — 8 HPLC2112 Glucose [BMIM][Cl] YbCl3 160 1 h — 20 HPLC3112 Glucose [HexMIM][Cl] YbCl3 160 1 h — 19 HPLC4112 Glucose [OMIM][Cl] YbCl3 160 1 h — 22.5 HPLC

a [BMIM][Cl], 1-ethyl-3-methylimidazolium chloride; [EMIM][Cl], 1-ethyl-3-methylimidazolium chloride; [OMIM][Cl], 1-octyl-3-methylimidazoliumchloride; [HexMIM][Cl], 1-hexyl-3-methylimidazolium chloride.

further decomposition in the first 15 min was observed, but forhigher reaction times the HMF selectivity started to decrease.Several lanthanide(III) chlorides (DyCl3, YbCl3, LaCl3, NdCl3,EuCl3) were tested in water, at 140 ◦C and for 15 min reaction.The final product was extracted with benzene. Lanthanide(III)chlorides were preferred compared to typical transition metalsbecause they are cheaper and less toxic, although they are notthe ideal catalysts for glucose dehydration (Table 9, entries 1-4). Since lanthanide ions have a high affinity for oxygen atoms,the authors believe that they coordinate with glucose and act asLewis acid catalysts.

Recently,112 lanthanide(III) chlorides were again tested ascatalysts for glucose dehydration to HMF, but this time usingionic liquids as solvents. Firstly, the HMF stability was testedin different ionic liquids at 100 ◦C, and all the ionic liquidstested showed some HMF degradation. The imidazolium-basedionic liquids with halides as anion showed the lowest degreeof degradation. Secondly, several lanthanide chlorides weretested as catalysts for glucose dehydration in two different ionicliquids, [BMIM][Cl] and [EMIM][Cl], and an improvement wasobserved when lanthanide chlorides was present as catalysts. Thestrongest Lewis acid, YbCl3, gave the highest yield, althoughstill moderate HMF yields (Table 9, entries 1–4). The authorssuggested that this reaction takes place by a different mechanismfrom the chromium chloride catalytic system, because the yieldwas favoured in hydrophobic ionic liquids, while the yield of theCr-catalysed version decreased with the hydrophobicity of theionic liquids.

4.2.4 Other metal catalysts. Armaroli et al.113 reported theuse of commercial niobium phosphates, or niobium catalystsprepared by treatment of niobic acid with phosphoric acid,for catalysis of sugar dehydration reactions. Substrates suchas fructose, sucrose and inulin were tested in aqueous media.It was observed that the HMF selectivity was very high forlower reaction times, but sugar conversion rates were low(Table 10, entries 1–4). For higher reaction times, although thesugar conversions increased up to 65.5%, the HMF selectivitydecreased, due to the formation of polymeric by-products.113

To overcome this problem, the authors reported an extractionprocess with MIBK as extraction solvent, where it was possibleto recycle both the residual aqueous substrate solution and thesolid catalyst, with fructose and inulin substrates (Table 10,entries 3 and 4). The conversion values increased to 60–75%and the HMF selectivity continued high, up to 98% (Table 10,entries 3 and 4).

A glucose transformation to HMF using a niobium catalystwas published in a patent in 2009.114

Although the main objective was to synthesize 2,5-furandicarboxylic acid (FDA), Ribeiro et al.65b reported aninitial reaction in which fructose was dehydrated to HMFwith moderate fructose conversion yields and good HMFselectivity. The compounds cobalt acetylacetone (Co(acac)3),SiO2-gel, and Co(acac)3 encapsulated in sol–gel (Co-gel) weretested as catalysts. A triphasic reaction was performed, fructosewas dissolved in water with MIBK as extraction solvent,and a heterogeneous catalyst was used. SiO2-gel give the bestHMF selectivity (Table 10, entries 5 vs. 6). These results wereimproved to 100% selectivity despite moderate conversion, whenthe reaction was made in water in an autoclave (Table 10,entry 7).

Vanadyl phosphate (VOP) was used as an acid catalystin the dehydration of fructose aqueous solutions to HMF.115

This catalyst showed low selectivity and moderate fructoseconversion (Table 10, entry 8). It was reported115 that acidity ofVOP can be modified by isomorphous substitution of some VO3+

groups with trivalent metals M3+ such as Fe3+, Cr3+, Ga3+, Mn3+

and Al3+. These new catalytic systems were tested in aqueoussolutions (Table 10, entries 10–12). FeVOP showed the bestperformance, even at high fructose concentrations (Table 10,entries 9–12), without the formation of insoluble polymeric by-products or HMF rehydration compounds. Similar activity andselectivity results were obtained with inulin as substrate, andFeVOP as catalyst (Table 10, entry 13).

Several metal chlorides were screened in a ionic liquid([BMIM][Cl], 1-butyl-3-methylimidazolium chloride), with theobjective of finding the best catalyst for fructose dehydration atroom temperature.62 Tungsten salts provided the best HMF yield(Table 10, entries 17 and 18). Several ionic-liquid-immiscible andlow-boiling organic solvents were tested as extraction solvents(Table 10, entries 18–20). THF provided a biphasic reactionwith higher HMF yields than the ionic liquid system (Table 10,entry 17 vs. 18). It was possible to isolate the HMF product withTHF as the extraction solvent, and the ionic liquid–catalystcould be recycled. Also a continuous batch process for theconversion of fructose to HMF in a THF–[BMIM][Cl] biphasicsystem was developed (Fig. 3), and tested with a bigger amountof fructose (10 g) as starting material.62

A screening was performed in DMSO with different metalcatalysts (100 ◦C, 3 h) for glucose dehydration.61b The bestwere chromium, aluminium and tin chlorides, the latterbeing the most efficient. With this catalyst several ionic


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 10 Conversion of carbohydrates to HMF promoted by miscellaneous catalystsa


Entry(ref.) Biomass source Solvent Catalyst Temp. (◦C) Time

Conversion(%)

HMFselectivity (%)



1113 Fructose (6 wt.%) H2O H3PO4-treatedniobic acid(P/N1)

100 0.5 h 31.2 93.3 GC —

1 h 33.3 30.32 h 61.5 12.4

2113 Fructose (6 wt.%) H2O Niobiumphosphate(NP2)

100 0.5 h 28.8 100.0 GC —

1 h 29.3 85.22 h 33.3 71.9

3113a Fructose (6 wt.%) H2O Niobiumphosphate(NP2)

100 0.5 h 33.6 98.3 GC Catalyst recycledwith MIBKextraction

1 h 75.8 97.84113a Inulin (6 wt.%) H2O Niobium

phosphate(NP2)

100 0.5 h 25.2 77.5 GC Catalyst recycledwith mibkextraction

1 h 48.7 74.01.5 h 76.3 72.0

5 65b Fructose H2O/MIBK Co-gel 88 8 h — 46 HPLC/RI —6 65b Fructose H2O/MIBK SiO2-gel 88 8 h — 47 HPLC/RI —7 65b Fructose H2O SiO2-gel 160

(20 bar)1.1 h 52 100 HPLC/RI —

8115 Fructose (30 wt.%) H2O VOP 80 0.5 h 45.1 32.9 GC–MS —2 h 65.2 35.8

9115 Fructose (6 wt.%) H2O FeVOP 80 2 h 48.1 42.2 GC–MS —10115 Fructose (10 wt.%) H2O FeVOP 80 2 h 60.9 51.2 GC–MS —11115 Fructose (30 wt.%) H2O FeVOP 80 1 h 70.8 59.6 GC–MS —12115 Fructose (40 wt.%) H2O FeVOP 80 0.5 h 57.7 87.3 GC–MS —13115 Inulin (6 wt.%) H2O FeVOP 80 2 h 41.8 82.7 GC–MS —14115 Fructose (6 wt.%) H2O CrVOP 80 1 h 60.0 48.5 — —15115 Fructose (6 wt.%) H2O AlVOP 80 1 h 75.9 57.6 — —16115 Fructose H2O VOP–TiO2 80 0.5 h 35.5 93.2 GC–MS —

1 h 39.7 87.41762 Fructose (20 wt.%) [BMIM][Cl] WCl6 50 4 h — 63 THF extraction Catalyst/solvent

recycling1862 Fructose (20 wt.%) [BMIM][Cl] /

THFWCl6 50 4 h — 72 THF extraction Catalyst/solvent


MIBKWCl6 50 4 h — 61 MIBK extraction Catalyst/solvent


EtOAcWCl6 50 4 h — 59 EtOAc extraction Catalyst/solvent

recycling2161b Glucose (17 wt.%) [EMIM][BF4] SnCl4 100 3 h 98 62 EtOAc extraction Catalyst/solvent

recycling for atleast 4 cycles

(20 wt.%) 99 61(23 wt.%) 100 61(26 wt.%) 99 58

2261b Fructose [EMIM][BF4] SnCl4 100 3 h 100 62 EtOAc extraction —2361b Sucrose (17 wt%) [EMIM][BF4] SnCl4 100 3 h 100 65 EtOAc extraction —2461b Cellobiose [EMIM][BF4] SnCl4 100 3 h 100 57 EtOAc extraction —2561b Starch [EMIM][BF4] SnCl4 100 3 h 100 47 EtOAc extraction —

a FeVOP, iron vanadyl phosphate [BMIM][Cl], 1-ethyl-3-methylimidazolium chloride; [EMIM][Cl], 1-ethyl-3-methylimidazolium chloride; DMSO,dimethyl sulfoxide; MIBK, methyl isobutyl ketone; Co-gel, cobalt acetylacetonate encapsulated in sol–gel silica.

liquids were tested, and it was observed that for ionic liquidsbased on anions having coordination abilities, such as chlo-ride, bis(trifluoromethane)sulfonimide (NTf2), trifluoroacetate(TFA), trifluoromethylsulfonate (OTf) or saccharin (SAC), theHMF yields were lower than with other type of anions (e.g. BF4

– tetrafluoroborate). The authors suggested that these anionscould compete with the interaction of glucose and the Snatom, inhibiting the HMF formation. The ionic liquid with

best selectivity was the [EMIM][BF4] (Table 10, entry 21).Based on this and other experimental evidence, the authorsproposed a mechanism involving a five- or six-membered ringchelate complex of the Sn atom and glucose (Scheme 15). Othersaccharides were also tested, such as sucrose, cellobiose, inulinand starch, providing reasonable HMF selectivity (Table 10,entries 22–25).61b After product extraction with ethyl acetate, itwas possible to recycle the SnCl4–[EMIM][BF4] catalytic system.


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Fig. 3

Scheme 15 61b.

5 Synthetic applications of HMF

The structural motifs present in HMF, namely furan, pri-mary hydroxyl and formyl functionalities, allows synthetictransformation to other target molecules using the followingmain transformations: selective oxidation and reduction of theformyl, hydroxyl groups and furan ring; carbonyl and hydroxylhomologation; and whole-skeleton transformations.

5.1 Oxidation

The oxidation of HMF can be performed selectively tothe formyl or hydroxyl groups to form 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) and 2,5-diformylfuran (DFF)respectively, or can involve both groups to give 2,5-furandicarboxylic acid (FDA), which are compounds of con-siderable interest as well as starting materials for furthertransformations and chemical building blocks for industry15,116

(Scheme 16).

Scheme 16

5.1.1 Selective oxidation of the formyl group. There areseveral examples in the literature for the selective oxidationof the formyl group of HMF to HMFCA (Scheme 17) byusing silver oxide 7c,117 or mixture of silver and copper(II)

Scheme 17

oxides118 under basic conditions. Gorbanev et al.119 reportedthe formation of HMFCA as an intermediate product duringthe aerobic oxidation of HMF to FDA with Au/TiO2 catalyst inbasic aqueous solution at room temperature. They studied therelationship between the formed products and the amount ofbase or applied O2 pressure, and observed that lower pressures orlow concentrations of base afforded more of the intermediate ox-idation product HMFCA compared to FDA. Casanova et al.120

also observed the formation of HMFCA as a intermediateproduct during gold-nanopracticle-catalyzed aerobic oxidationof HMF. They described that selective oxidation to HMFCAtook place at 25 ◦C after 4 h and reported 100% yield. Veryrecently, Davis et al.121 described 92–93% selectivity towardsHMFCA with 100% conversion of HMF promoted by Au/Cand Au/TiO2 in basic conditions. Van Deurzen et al.122 oxidizedHMF with H2O2 and chloroperoxidase (CPO), which is anenzyme known to be an effective catalyst for various oxidationreactions with H2O2. They observed formation of DFF as amajor product and unexpected formation of HMFCA as aminor product in up to 40% yield.

5.1.2 Selective oxidation of the hydroxyl group. The selec-tive oxidation of hydroxyl group of HMF leads to the formationof DFF, which is an important monomer for industry.123

Numerous examples in the literature have described the selectiveoxidation of the hydroxyl group of HMF to DFF using diverseoxidants.

Reijendam et al. (Table 11, entry 1) obtained DFF in 37% yieldby using lead diacetate in pyridine. Morikawa oxidized HMFwith a variety of oxidants and reported higher yields (Table 11,entries 2–5). Cottier et al. obtained DFF in 58% yield by usinga DMSO–potassium dichromate oxidative complex at 100 ◦C.They observed that the application of ultrasonic irradiation tothe reaction mixture afforded DFF in higher yield 75% (Table 11,entry 7). The trimethylammonium chlorochomate (TMACC)–Al2O3 oxidative system was also tested in conventional andunder sonochemical conditions, providing DFF in 75% and 72%respectively (Table 11, entry 8). The same authors performed ox-idation of HMF adsorbed together with pyridinium chlorochro-mate (PCC) on Al2O3, and obtained DFF in 58% yield (Table 11,entry 9). McDermott and Stockman also performed oxidationwith PCC in CH2Cl2 and reported slightly higher yield (Table 11,entry 10). Quantitative yield was obtained by Mehdi et al., whoperformed oxidation of HMF with (NH4)2[Ce(NO3)6] (CAN)in the ionic liquid [EMIM][OTf] (1-ethyl-3-methylimidazoliumtrifluoromethylsulfonate) as a solvent (Table 11, entry 11). DFFwas obtained via CPO-catalyzed oxidation of HMF with H2O2.Optimum activity for the oxidation of HMF was observed at pH5, providing 89% conversion and 59% selectivity. The highestselectivity 74% was observed at pH 3 with 25% conversionof HMF (Table 11, entry 12). Cotier et al.124 (Table 11,entry 13) reported the oxidation of HMF with 4-substituted


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 11 Examples of oxidation of HMF to DFF using differentoxidants

Entry Reaction conditions Yield (%)

1125 Pb(OAc)2, pyridine 372126,127 CrO3, pyridine 73, 683128 Ac2O, DMSO 764128 HNO3, DMSO 31–675128 N2O4, DMSO 766117 BaMnO4 937129 K2Cr2O7, DMSO, ultrasonic irradiation 758129 TMACC, Al2O3, ultrasonic irradiation 72915,130 PCC, Al2O3, ultrasonic irradiation 5810131 PCC, CH2Cl2 6511132 [EMIM][OTf], CAN, 100 ◦C 10012122 CPO/H2O2

a

13124 4-Benzoyloxy-TEMPO, Ca(ClO)2 8114133 Dess–Martin periodinane 74

a 89% conversion of HMF and 59% selectivity.

2,2,6,6-tetramethylpiperidine-1-oxide (TEMPO) free radicalsand supporting co-oxidants. The best co-oxidant was found to becalcium hypochlorite in the presence of 4-benzoyloxy-TEMPO,providing 81% yield. Dess–Martin oxidation of HMF was alsofound to be effective, providing DFF in 74% yield (Table 11,entry 14).

Several authors have investigated the conversion of HMFto DFF with oxygen, air or other economical and environ-mentally friendly oxidants using various metal-based catalysts.Partenheimer and Grushin134 reported the oxidation of HMFto DFF by using Co/Mn/Zr/Br or Co/Mn/Br catalysts andair as oxidant. They observed that Co/Mn/Zr/Br was the moreactive, providing higher conversion and selectivity. As expected,under comparable reaction conditions the conversion increasedwith temperature. (Table 12, entry 1). Carlini et al. (Table 12,entry 2) oxidized HMF to DFF in a biphasic water–methylisobutyl ketone (MIBK) system or in pure organic solvents usingvarious metal-modified unsupported or SiO2-supported vanadylphosphate (VOP) catalysts under O2 or air pressure. The authorsreported up to 10% conversion and selectivity of 60–100%when water–MIBK was the reaction medium. Higher conversionrates were obtained in only MIBK as a solvent but with lowerselectivity (98% conversion and 50% selectivity). DMF wasfound to be the best solvent for this transformation, providingup to 84% conversion and 97% selectivity. Amarasekara et al.reported the conversion of HMF to DFF at room temperaturewithout formation of FDA using NaClO as oxidant andcatalyzed by Mn(III)-salen catalysts. Oxygen and H2O2 werealso tested as more economical oxidants but both failed togive DFF in the presence of Mn(III)-salen catalyst (Table 12,entry 3). Cu and V catalysts supported in poly(4-vinylpyridine)crosslinked with 33% divinylbenzene (PVP) were tested for theheterogeneous catalytic aerobic selective oxidation of HMF.They provided higher activity and better chemoselectivity thanthe corresponding homogeneous catalysts, when the appropriatesolvent was used for the reaction. The authors also observedthat V-containing polymeric catalysts were more active thanthose containing Cu (Table 12, entry 4). Lilga et al. patenteda method based on activated MnO2 oxidation of HMF toDFF in good yields (Table 12, entry 5). Various inorganicvanadium compounds, such as V2O5 and VOHPO4·0.5H2O,

efficiently catalyzed air oxidation of HMF to DFF. This kind ofV catalyst was found to be active for air-oxidation of not onlypure HMF but also HMF produced via dehydration of fructose.It was observed that the least expensive and most readilyavailable catalyst that was used, V2O5, exhibited one of thehighest efficiencies for the process, providing DFF in 58% yieldcalculated on HMF and 43% calculated on fructose. The bestresult was observed for VOHPO4·0.5H2O (61% and 45% yieldrespectively) (Table 12, entry 6). Very detailed studies on air orO2 oxidation of HMF promoted by supported platinum catalystsin aqueous solutions were recently reported by Lilga et al. Theyobserved good conversion to DFF by using Pt/SiO2 catalystand air as oxidant in neutral solution. Similar conversion andselectivity were achieved with Pt–ZrO2 and air in acidic solution(Table 12, entries 7 and 8).

The electrochemical oxidation of HMF carried out in adivided cell at a platinum anode in a biphasic H2O–CH2Cl2

system was reported by Skowronski et al.140 Various salts weretested as supporting electrolytes. The best yield was 68%,obtained by using Na2HPO4 for 7 h.

The indirect oxidation of HMF providing DFF in 91%yield has been performed via initial protection of the hydroxylgroup with 5-tert-butyldimethylsilyl (1a) and 5-trimethylsilyl(1b) groups, followed by oxidation with N-bromosuccinimide(NBS) in the presence of azobisisobutyronitrile (AIBN)141

(Scheme 18).

Scheme 18

5.1.3 Oxidation of the formyl and hydroxyl groups. HMFis a widely exploited precursor for the synthesis of FDA(Scheme 19), which is a potential biorenewable replacementmonomer for terephthalic acid in polyethylene terephthalateplastics, and has been described as one of the building blocks ofthe future.116

Scheme 19

Morikawa128 oxidised HMF to FDA using N2O4 in DMSOand nitric acid in DMSO. El-Hajj et al.117 used nitric acid for thistransformation and obtained FDA in 24% yield. The authors


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 12 Oxidation of HMF to DFF using metal catalysts

Entry (ref.) Reaction conditions HMF conversion (%) DFF selectivity (%)

1134 Co/Mn/Br/Zr or Co/Mn/Br, air (70 bar), 50–75 ◦C, 2 h 60–99 38–732135 VOP or MVOP, O2 or air, 80–150 ◦C Up to 98 Up to 993136 Mn(III)-salen–NaClO, RT 89a 1004137 Cu- or V-based catalysts, DMSO, air, 130–160 ◦C. Up to 85 Up to >995138 MnO2, CH2Cl2, reflux, 8 h 80 100687b VOHPO4·0.5H2O, DMSO, air (1 atm), 150 ◦C 61a —7139 5% Pt–SiO2, air (150 psi), 60–100 ◦C 60 708139 5% Pt–ZrO2, air (150 psi), 100 ◦C, 40% AcOH 50 70

a DFF yield.

reported higher yields by using Ag2O and HNO3 or KMnO4

as oxidants (47% and 70% respectively). Cottier et al.15,130 alsoused nitric acid as oxidant and observed the formation of FDAand 5-formyl-2-furancarboxylic acid, which was resistant tofurther oxidation under these conditions. The ratio betweenthe products was found to be dependent on the reactionconditions.

Several authors have published and patented methods forthe oxidation of HMF to FDA using more economical andenvironmentally friendly oxidants and heterogeneous metalcatalysts. Vinke et al.142 reported the oxidation of HMF to FDAin near-quantitative yield under basic reaction conditions usingPt/Al2O3 as catalyst at 60 ◦C. Air oxidation of HMF catalyzedby Co/Mn/Br/Zr or Co/Mn/Br resulted in the formation ofFDA in up to 61% yield and 2-carboxy-5-formylfuran as a minorproduct in up to 3% yield.134 It was observed that the yieldincreased with the catalyst concentration and temperature, butnot with the addition of Zr to the Co/Mn/Br. Lew118 patentedan oxidation method using a platinum catalyst adsorbed onactivated charcoal in basic aqueous solutions and bubblingoxygen through the solution, providing the corresponding acid(FDA) in 95% yield. Lilga et al.138 patented a method forthe synthesis of FDA from HMF using Pt–ZrO2 and air,claiming 100% conversion and 98% selectivity. Gorbanev et al.119

oxidized HMF to FDA in up to 71% yield using commercialheterogeneous Au/TiO2 nanoparticle catalyst in aq. NaOH at 20bar O2 and ambient temperature. The authors described also theinfluence of oxygen pressure and the amount of hydroxide basedon the selectivity and yield. Casanova et al.120 carried out thistransformation using gold nanoparticle catalysts with varioussupports in basic aqueous conditions. The oxidative pathwaystarts with the fast oxidation of HMF into HMFCA, and therate-limiting reaction step was the oxidation of HMFCA intoFDA. Au–CeO2 and Au–TiO2 catalysts were found to be themost active, providing FDA in >99% yield. Under optimizedreaction conditions (10 bar of O2, 130 ◦C and an NaOH/HMFmolar ratio of 4), it was shown that Au–CeO2 provides higheractivity and selectivity for FDA. Reduced substrate degradationand increased lifetime of the catalyst was observed by perform-ing the reaction using a two-step procedure – first at 25 ◦C for 4h followed by 130 ◦C for 3 h. Screening of supported platinumcatalysts at different pH in a flow reactor was performed by Lilgaet al.139 They obtained nearly quantitative yields of FDA usingstoichiometric aqueous Na2CO3, with air or O2 over Pt/C orPt/Al2O3, and 98% selectivity with 100% conversion of HMFover Pt–ZrO2 at neutral pH with air. The best result under acidic

conditions (85% selectivity and 100% conversion) was achievedwith O2 and Pt–ZrO2. Very recently, Davis et al.121 described O2

oxidation of HMF to FDA promoted by supported Pt, Pd andAu catalysts under basic aqueous conditions. They observed thatPt/C and Pd/C were more selective towards FDA compared toAu/C and Au/Ti2O under identical conditions, providing 79%and 71% selectivity respectively with 100% conversion of HMFafter 6 h. Higher pressures of O2 and concentrations of basewere required for Au catalysts, resulting in up to 80% selectivityand 100% conversion after 22 h.

A supported gold nanoparticle catalyst was also foundto be effective for aerobic oxidative esterification of HMF(Scheme 19). Taarning et al.143 reported the formation ofdimethyl furan-2,5-dicarboxylate (DFD) in excellent yield at130 ◦C in MeOH and in the presence of an Au/TiO2 catalystand basic conditions. When the reaction was carried out at roomtemperature, the oxidation took place only at the formyl group,and 5-hydroxymethyl methylfuroate (HMMF) was obtained inexcellent yield.

More recently, Casanova et al.144 described a one-pot base-freeaerobic oxidative esterification of a methanol solution of HMFto dimethyl furan-2,5-dicarboxylate (DFD) by using a Au–CeO2

catalyst, which could be recovered and reused with small loss ofactivity but maintaining high selectivity. It was observed thatthe temperature and the substrate-to-catalyst ratio affect thereaction rate, but nevertheless a quantitative yield of DFD wasalways obtained.

5.1.4 Oxidation of the furan ring. Oxidation of the furanring of HMF can take place under photo-oxygenation con-ditions. When alcohol was used as a reaction medium, theoxidation takes place via the formation of an endoperoxidefollowed by the attack of an alcohol on the formyl group oron the 5-position of the furan ring, leading respectively tohydroxybutenolide 2 (Scheme 20, route a) as a major product oralkoxybutenolide 3 (Scheme 20, route b) as a minor product.145

In addition, Marisa et al.146 reported the photochemicaloxidation of HMF in water providing 5-hydroxy-4-keto-2-pentenoic acid 4 (Scheme 21), which is a possible intermediateor monomer for the chemical industry.

5.2 Reduction

5.2.1 Reduction of the furan ring and/or formyl group.Selective reduction of the formyl group of HMF leads to for-mation of 2,5-bis(hydroxymethyl)furan 5, which is an importantchemical building block used in the production of polymers and


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Scheme 20

Scheme 21

polyurethane foams.16 Several reports described the reductionof HMF to 5 with sodium borohydride in high yields.147 Turneret al.148 reported the synthesis of 5 in 76.9% yield by usingformalin and aq. NaOH. Nickel, copper chromite, platinumoxide, cobalt oxide, molybdenum oxide and sodium amalgamcatalysts were found to be effective for this transformation.12,15

Hydrogenation of HMF in aqueous media in the presence ofnickel, copper, platinum, palladium or ruthenium catalysts havebeen studied.149 2,5-Bis(hydroxymethyl)furan was obtained asthe main product when copper and platinum catalysts wereused. 100% conversion and selectivity towards 5 was observed byusing Pt/C, PtO2 or 2CuO·Cr2O3, while the presence of Pd/C149

or Raney R© nickel148–150 catalysts resulted in hydrogenation ofthe furan ring, 2,5-bis(hydroxymethyl)tetrahydrofuran 6 beingformed as the major product in high yield (Scheme 22).

Scheme 22

5.2.2 Reduction of the formyl and hydroxyl groups. Re-duction of both the formyl and hydroxyl groups in HMFis one of the synthetic pathways for the synthesis of 2,5-dimethylfuran 7, which is of particular interest because of itshigh energy content and potential use as a biofuel.60b Roman–Leshkov et al.60b recently reported a two-step process for theproduction of 7. They subjected HMF (obtained from D-fructosein biphasic reactor) to hydrogenation over a carbon-supported

copper/ruthenium (CuRu/C) catalyst, and obtained 7 in verygood yields (76–79%).

Two years later, Binder et al.103 reported the hydrogenolysisof crude HMF from corn stover in the presence of CuRu/C,providing 7 in 49% yield. Liujkx et al.151 described in the sameyear the formation of 7 by the hydrogenation of HMF in thepresence of palladium catalyst.

Very recently, Chidambaram and Bell61d reported the hydro-genation of either neat HMF or HMF obtained by dehydrationof fructose in a mixture of 1-ethyl-3-methylimidazolium chloride(EMIMCl) and acetonitrile promoted by carbon-supportedtransition metals. They observed the formation of a series ofproducts, and in particular 2,5-dimethylfuran. A Pd/C catalystwas found to be the most active, providing 7 in 16% yield with47% HMF conversion (Scheme 23).

Scheme 23

5.3 Transformations of the formyl group

5.3.1 Reductive amination. Villard et al.152 reported amethod for the reductive amination of HMF with L-alanineor D-alanine in aq. NaOH in the presence of Raney R© nickel. Theresulting (R)- or (S)-N-(1-carboxyethyl)-2-(hydroxymethyl)-5-(methylamino)furan 8 was isolated in 38% yield as the ammo-nium salt (Scheme 24).

Scheme 24

The synthesis of 2-(hydroxymethyl)-5-(aminomethyl)-furan 9in 72% yield as an intermediate for further transformations wasperformed by the reductive amination of HMF and liq. NH3

in presence of Raney nickel.153 Using the same catalyst butswitching from liq. NH3 to aq. MeNH2, 2-(hydroxymethyl)-5-(methylaminomethyl)furan 10 was obtained in an excellent yieldof 91%153b (Scheme 25).

Scheme 25

Cukalovic and Stevens58 recently reported a procedure forthe synthesis of several 5-aminomethyl-2-furfuryl alcohols invery good yields starting from HMF and aromatic or aliphaticprimary amines. The reaction was performed by the in situreduction with NaBH4 of the initially yielded aldimines. Waterand bio-based solvents such as methanol and ethanol weretested as reaction media, as well as conventional and microwave


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


heating, which resulted in the increase of the reaction ratecompared to the room-temperature reactions. (Scheme 26).

Scheme 26

Kojiri et al.154 patented a method where they claimed thesynthesis of novel indolopyrrolocarbazole derivatives and theirstudies as antitumor agents. The HMF derivative 11 wasachieved via two-step reductive amination (Scheme 27).

Scheme 27

Resin-bound compound 12 was obtained via reductive ami-nation of HMF by Sun and Murray155 and used for subsequentDiels–Alder transformations (Scheme 28).

Scheme 28

5.3.2 Wittig-type reactions. A one-pot fluoride-promotedWittig reaction of HMF was reported by Fumagalli et al.156 Thecorresponding ethyl 3-(5-(hydroxymethyl)furan-2-yl)acrylate 13was obtained in 81% yield and 85% diastereoselectivity for theE isomer (Scheme 29).

Scheme 29

The same compound was synthesized in 90% yield (and theE configuration), via a Wittig–Horner reaction with ethyl 2-(diethoxyphosphoryl)acetate157 (Scheme 30).

HMF has been subjected to Taylor’s tandem oxidation–Wittigprocedure by McDermott and Stockman,131 providing diester 14in 87% yield in one step after 4 days as a 6.6:1 mixture of E,Eand E,Z isomers (Scheme 31).

Scheme 30

Scheme 31

Goodman and Jacobsen158 performed the 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-mediated Horner–Wadsworth–Emmons reaction of HMF with phosphonateimide 15. The reaction was carried out in THF, providingN-[3-(5-hydroxymethylfuran-2-yl)acryloyl]benzamide 16 invery good yield (87%). Water was also described as a solvent,obviating any need to run the reaction under an inertatmosphere (Scheme 32).

Scheme 32

Another Horner–Wadsworth–Emmons reaction of HMF as apart of a synthetic procedure for the synthesis of 3(5)-substitutedpyrazoles was performed in one step using NaH withoutisolation of the intermediate a,b-unsaturated tosylhydrazoneN-sodium salt 17 before the cyclization step. The final product,18, was isolated in 60% yield159(Scheme 33).

Scheme 33

5.3.3 Baylis–Hillman reaction. The Baylis–Hillman reac-tion of HMF with methyl acrylate using stoichiometric base andaqueous medium was reported by Yu et al.160 The correspondingproduct 19 was obtained in 62% yield after 36 h using 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalyst. One year later,Yu and Hu160b described the formation of compound 20 in 61%yield after 48 h using the same reaction conditions and acrylamide (Scheme 34).

Scheme 34


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


5.3.4 Acetal formation. Cottier et al.161 reported the re-action of HMF with trimethyl orthoformate in the presenceof ytterbium sulfate supported on Amberlite 15, providingthe corresponding [5-(dimethoxymethyl)-2-furyl]methanol 21in 80% isolated yield. A higher yield (96%) was achieved bythe condensation reaction of HMF and MeOH catalyzed bycalcined and dehydrated Al-b-zeolite (Si/Al = 12.5:1 molar ratio,CP806)144 (Scheme 35).

Scheme 35

The synthesis of 5-hydroxymethyl-2-furaldehyde bis(5-formylfurfuryl) acetal 22 by using a strong-acid cation-exchangeresin as catalyst was patented by Terada et al.162 The authorsclaimed 2.3% yield of 22 and its application for the preparationof flavor-improving agents (Scheme 36).

Scheme 36

The formation of the cyclic acetal 23 was achieved byUrashima et al.163 by a condensation reaction of levogalactosanand HMF at 100 ◦C (Scheme 37).

Scheme 37

5.3.5 Aldol condensations. Several authors reported thealdol condensation reactions of HMF as a synthetic strategyfor the synthesis of biologically active compounds and usefulintermediates for the synthesis of biofuels.164

The aldol condensation reaction between HMF and acetophe-none was performed in water or methanol in the presence ofbase, providing 5-(hydroxymethyl)furfurylidene acetophenonein 80 and 82% yield respectively.165

The synthesis in 91% yield of naturally occurring furanderivative rehmanone C 24, which has displayed significantbiological activity, was described by Quiroz-Florentino et al.166

using a base-catalyzed aldol condensation with 2 equivalents ofacetone and HMF. The same reaction conditions, but using 0.5equivalents of acetone, provided the bis-derivative 25 in 60%yield within 2 h (Scheme 38).

Another aldol condensation reaction of HMF towards thesynthesis of biologically active compounds was reported by

Scheme 38

Hanefeld et al.,167 who described a method for the synthesisof rhodanine derivative 26 in 73% yield (Scheme 39).

Scheme 39

Shinobu et al.168 reported the synthesis of 3-((5-(hydroxymethyl)furan-2-yl) methylene)-N-acetyl-2-oxoindoline27 by using the reaction between HMF and N-acetyloxindolecatalyzed by piperidine (Scheme 40).

Scheme 40

The aldol reaction of HMF under microwave irradiationin the presence of KF/Al2O3 was described by Suryawanshiet al.169 They obtained chalcone 28 in 76% yield and studied itsantileishmanial activity (Scheme 41).

Scheme 41

The synthesis and photochemistry of HMF chromonederivative 30 was investigated.170 The compound 30 wasobtained by using a piperidine-catalyzed aldol condensationof 1-(2-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)propane-1,3-dione 29 with HMF followed by SeO2 oxidation; aDBU-induced condensation was also studied as a simpler andmore efficient pathway (Scheme 42).

The synthesis and cytotoxicity studies of two HMF curcuminanalogues, 32 and 33, was reported.171 Boric anhydride wasfirst added to the reactions in order to form a complex with2,4-pentanedione or compound 31 in order to protect the C-3 position from Knoevenagel condensation in such way thataldol condensation takes place only at the terminal carbons.The target compounds 32 and 33 were obtained in 12% and 32%yield respectively (Scheme 43).


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Scheme 42

Scheme 43

5.3.6 Other reactions. There are a considerable number ofliterature examples of the reaction of the formyl group of HMFwith amine-based compounds. Formation of arylhydrazones34,172 semioxamazone 35,173 semicarbazone 36174 and thiosemi-carbazone 37175 have been reported (Scheme 44).

Scheme 44

The reaction of HMF with aromatic amines leads to forma-tion of Schiff bases such as b-naphthylamine 38,176 Schiff basesand azomethine salts177 (Scheme 45).

Scheme 45

The conversion of HMF to its oxime derivative 39178

(Scheme 46) in 95% yield has been described, and some biolog-ically active HMF proline-oxime-containing peptide derivativeswere also reported and studied.179

Scheme 46

The reactions of HMF with 1,2-aminothiols leads to theformation of new heterocyclic systems. Undheim et al.180 re-ported the synthesis of thiazolidine derivative 40 in 90% yield,by reaction of L-cysteine methyl ester and HMF in the presenceof potassium acetate. Benzothiazole derivative 41 was obtainedin quantitative yield from HMF and 2-aminobenzenethiol in thepresence of acetic acid181 (Scheme 47).

Scheme 47

The synthesis and studies of insecticidal activities of neon-icotinoid 42 was reported from Shao et al.182 The final prod-uct was isolated as its hydrochloric acid salt in 72% yield(Scheme 48).

Scheme 48

Karaguni et al.183 reported a novel HMF indene derivative44 with anti-proliferative activity, obtained in 45% yield via aone-step condensation protocol using 5-fluoro-2-methylindene-3-acetic acid 43 (Scheme 49).

Scheme 49

An adenosine receptor (A2A) antagonist, HMF derivative45, was obtained by a three-component reaction of HMF184

(Scheme 50).The condensation reaction between HMF and 2,3,4,5-

tetrahydropyridine was reported by Miller, providing the E-configured derivative 46 in 64% isolated yield185 (Scheme 51).


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Scheme 50

Scheme 51

Baliani et al.186 described a method for the conversion of thealdehyde function of HMF into nitrile 47 in a very good yieldof 80% by using iodine in aqueous ammonia (Scheme 52).

Scheme 52

Ramonczai and Vargha187 performed the reaction of HMFand diazomethane, providing 5-hydroxymethyl-2-acetofuran 48in 40% yield (Scheme 53).

Scheme 53

HMF was selectively carbonylated to 5-formylfuran-2-aceticacid 49 in acidic aqueous media using a water-soluble palla-dium complex of trisulfonated triphenylphosphine (TPPTS) ascatalyst.188 The only observed byproduct was 5-methylfurfural50 formed from the reduction of HMF. The activity andselectivity of the carbonylation was found to be influenced bythe Pd/TPPTS molar ratio. The best efficiency was observedfor Pd/TPPTS = 6, which gave 90% conversion and 71.6%selectivity. The relationship between the selectivity and thenature of the anion of the acid component was also studied.Acids of weakly or non-coordinating anions (such as phospho-ric, trifluoroacetic, 4-toluenesulfonic and sulfuric acids) favorcarbonylation, giving 49 as the main product, while the acidsof strongly coordinating anions (such as HBr and HI) decreasethe selectivity. In agreement with this, 50 was the only observedproduct when HI was used (Scheme 54).

5.4 Reactions of the hydroxyl group

5.4.1 Formation of halides. Halogen substitution of thehydroxyl group of HMF can be easily performed, resultingin the formation of 5-halomethylfurfurals (Scheme 55), usefulintermediates for the synthesis of HMF derivatives due to theirhigh reactivity.

Several synthetic protocols for the synthesis of 5-chloromethyfurfural 51 have been described in the literature.Treatment of HMF with gaseous or 36% aq. HCl in various

Scheme 54

Scheme 55

organic solvents led to the formation of 51 in moderate to verygood yields (Table 13, entry 1). Sanda et al. reported a method forthe synthesis of 51 with similar yields using chlorotrimethylsilaneand CHCl3 or DMSO–Et2O as solvents, but CHCl3 was foundto be the best (Table 13, entry 2). Very detailed studies on theVilsmeier reaction as a synthetic pathway for the synthesis of 51was reported by Sanda et al. Various reaction conditions andactivating reagents were tested (Table 13, entries 3–5). DMFwas found to be the best solvent for this reaction. The authorsalso reported preparative-scale experiments, and studied theinfluence of different co-solvents, HMF concentrations and therate of the POCl3 addition.

Screening of SOBr2, PBr3 and PBr5 reagents for the synthesisof 5-bromomethyfurfural 52 was performed by Sanda et al.,and it was obtained in moderate yields (Table 14, entries 1–4).Excellent yields were achieved by the reaction of HMF withMe3SiBr, using CHCl3 or 1,1,2-trichloroethane as a solvent(Table 14, entries 5 and 6). The treatment of HMF with solutionof HBr in Et2O or aq. HBr in CCl4 resulted in the formation of52 in moderate yields (Table 14, entries 7 and 8).

5.4.2 Esterification. The hydroxyl group of HMF canundergo esterification reactions as a normal alcohol. Thereare several examples in the literature describing the formationof various aromatic HMF esters using the reaction of HMFwith the corresponding aromatic acid chlorides under basicconditions. Jogia et al.193 reported the formation of HMF

Table 13 Conversion of HMF into 51

Entry (ref.) Reaction conditions Yield (%)

17d,189 Gaseous or 36% aq. HCl 64–872189 Me3SiCl, CHCl3, 6 h 923190 SO2Cl2, DMF, 50 ◦C, 8 h 864190 POCl3, DMF, 5 ◦C, 5 h 925190 MeSO2Cl, DMF, 65 ◦C, 8 h 846189 SOCl2 537189 SOCl2 + pyridine 71


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 14 Conversion of HMF into 52

Entry (ref.) Reaction conditions Yield (%)

1189 SOBr2 632189 SOBr2 + pyridine 753189 PBr3 + Et3N 294189 PBr5 + CaCO3 625189,191 Me3SiBr, CHCl3 98,189 886189 Me3SiBr, CHCl2CH2Cl 997189,192 HBr, Et2O 64,189 408189 47% HBr, CCl4 70

ester derivatives 54a–c using reaction of HMF with aromaticacid chlorides 53a–c in pyridine in moderate yields (30–66%)(Scheme 56).

Scheme 56

Compound 54a was obtained in 84% yield by Bognar et al.194

using the same reaction at room temperature. The reaction ofacetic anhydride with HMF in the presence of NaOAc, leading toformation of 5-acetoxymethylfurfural in 81% yield, was reportedby Cottier et al.145c The synthesis of 5-propionoxymethylfurfural55 in 66% yield resulted from the reaction of propionic anhydrideand HMF. Compound 55 is an important fungicide,15 and itssynthesis was patented by Cope195 (Scheme 57).

Scheme 57

The author also claimed that the conversion can be modifiedby reacting HMF with propionic acid catalyzed by a smallamount of strong acid. The widely exploited DIC/DMAPprocedure was used by Gupta et al.196 for the esterification ofHMF and Sieber amide resin loaded with aliphatic dicarboxylicacids (Scheme 58). The resulting solid-phase-supported HMFesters were used for the combinatorial synthesis of furan-basedlibraries of compounds.

Scheme 58

5.4.3 Formation of ethers. The condensation reaction ofHMF with alcohols is a synthetic pathway which provides HMFether derivatives. Timko and Cram147c described the synthesis of5,5¢-diformylfurfuryl ether 56 from HMF in 44% yield usingazeotropic distillation of water and toluene in the presence of4-toluenesulfonic acid. Chundury and Szmant197 carried out

several experiments in order to obtain 56 in high yields. Differentsolvents and acidic catalysts were tested, using a Dean–Starktrap. The highest reported yield was 76% with 4-toluensulfonicacid as catalyst in the presence of P2O5. Formation of 56 in 38%yield was reported by Cottier et al.145c by refluxing HMF usinga Dean–Stark trap in benzene in the presence of ion-exchangeresin IR 120 (H+) (Scheme 59).

Scheme 59

The 5-(methoxymethyl)furan-2-carbaldehyde 57 and deriva-tive 58 were obtained in 50% and 24% yield respectively145a byusing the reactions of HMF with MeOH in the presence ofAmberlite IR 120 H+ for 57, and ethylene glycol with Py·HClcatalyst for 58 (Scheme 60).

Scheme 60

Oikawa et al.198 reported the synthesis of MPEG derivative ofHMF 59, which was used for further transformations in tandemUgi/Diels–Alder reactions. The reaction was carried out withiodine monochloride or MeOTf in the presence of molecularsieves, providing 88% or 75% yield respectively (Scheme 61).

Scheme 61

El-Hajj et al.199 reported the reaction between HMF and di-hydropyran catalyzed by pyridinium p-toluenesulfonate (PPTS),providing 5-(2-tetrahydropyranyl)oxymethyl furfural 60 in 72%yield (Scheme 62).

Scheme 62

The Lewis acid-catalysed rearrangement of glycals in thepresence of alcohols, known as the Ferrier reaction, wasused by Filho et al.200 to obtain a 2,3-unsaturated glyco-side ether derivative of HMF 61. Various catalytic systems


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


were tested, and the best yield of 93% was achieved usinga mixture of lithium tetrafluoroborate and tin(II) chloride.Both a- and b-anomers were formed, in a ratio of 85:15(Scheme 63).

Scheme 63

The synthesis of a b-glucopyranoside ether derivative of HMF(63b) in 32% yield after column chromatography was reportedusing the reaction between 62a/b and HMF in the presence ofBF3·Et2O.161 (Scheme 64).

Scheme 64

Several examples were reported for the formation of etherderivatives of HMF using the widely exploited Williamsonsynthesis, as presented in Table 15. Other examples for theprotection of the hydroxyl group of HMF are obtained as itstert-butyldimethylsilyl ether141,161,201 or trimethylsilyl ether141 inDMF using imidazole as catalyst.

5.4.4 Other reactions. The reaction of HMF with N,O-(bisphenoxycarbonyl)hydroxylamine 68 under Mitsunobu con-ditions, providing hydroxyurea derivative 69, was reported byLewis et al.203 (Scheme 65).

Scheme 65

Dow et al.204 described the reaction of HMF and diethylazodi-carboxylate (DEAD) using Mitsunobu-type reaction conditionsin the absence of other nucleophiles. Hydrazine derivative 70 wasobtained in 12% yield (Scheme 66).

Scheme 66

Cotier et al.145c reported the reaction of HMF and ben-zonitrile or acetonitrile catalyzed by trifluoromethanesulfonicacid resulted in 5-benzamidomethyl-2-furfural 71 and 5-acetamidomethyl-2-furfural 72 in 48% and 50% yield respec-tively (Scheme 67).

Scheme 67

The FeCl3-catalyzed Friedel–Crafts reaction of HMF with o-xylene, providing 37% yield and 62% regioselectivity for the4-alkylated product 73, was reported by Iovel et al.205 Theyexplained the moderate yield (compared to the much higheryields when other benzyl alcohols were used) due to the “self-arylation” of HMF during the reaction (Scheme 68).

Scheme 68

5.5 Furan ring reactions

Several synthetic transformations involving the furan ring inHMF have been reported. Oxidation and reduction reactionshave already been described in Sections 1.4 and 2.1.

5.5.1 Hydrolysis. It is known that cleavage of the furan ringof HMF takes place under acidic conditions.206 This process wasfound to be very important, especially when starting directlyfrom biomass due to the formation of levulinic acid (LA)as the final product. LA, together with its derivatives, areimportant chemical building blocks with various applicationssuch as production of fuels, fuel additives, and polymers.207

Two possible pathways were proposed by Horvat et al.208 forthis transformation. Pathway A goes via 2,3 water addition toHMF and leads to polymerization, while pathway B proceedsby 4,5 addition of water, resulting in the formation of 2,5-dioxo-3-hexenal 74, which fragments to levulinic 75 and formic acid(Scheme 69).

Scheme 69

A number of studies on the kinetics of acid-catalyzed HMFdegradation to LA have been reported using different acidcatalysts, acid concentrations and temperature ranges.209 Morerecently, very detailed kinetic studies on this process werereported by Heeres et al.210 The experiments were carried outwith various acid catalysts and acid concentrations between0.05–0.1 M in a temperature window of 98–181 ◦C. The effectof the initial concentrations of HMF was also studied in the


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 15 Williamson synthesis of HMF ester derivatives

Entry (ref.) Reaction conditions Product Yield

1166 MeI, NaH, THF, RT, 16 h 94%

2145c Benzyl bromide, Ag2O, DMF, RT, 53 h 72%

3161

CH2Cl2, Ag2O, RT, 5 h

11%

4202 Ph3CCl, pyridine, 40 min 4.5 ga

a Starting from 7.8 g of HMF.

range 0.1–1 M. The LA was obtained in yields up to 94% usingsulfuric acid as the catalyst.

The hydrothermolysis of HMF at 27.5 MPa and 290–400 ◦Cwas performed by Luijkx et al.,211 and resulted in 1,2,4-benezenetriol 76 as the major product in up to 46% yield and50% HMF conversion. The authors also described a possiblepathway for this transformation (Scheme 70).

Scheme 70

5.5.2 Synthesis of betaine salts. The synthesis of betainesalts from HMF with primary amines or amino acids isimportant, because they seem to be promising targets for furtherresearch due to their taste-modulatory activity.212 N-Methyl-3-oxidopyridinium betaine 77 was obtained via the one-stepreaction of HMF and MeNH2 in low yield (Table 16, entry 1).Much higher yield was achieved by Muller et al.,153b whoreported a two-step protocol for the synthesis of 77. First, theyperformed reductive amination to obtain 2-(hydroxymethyl)-5-(aminomethyl)furan 10, which was in turn exposed to brominein water to give 77 in good yield (Table 16, entry 2). Thesynthesis of 78 in moderate yields was performed in one stepin basic conditions (Table 16, entry 3). The betaine salt 79was obtained by the reaction of HMF and N-acetyllysine

by Pachmayr, and later by Koch, but the yields were notprovided (Table 16, entry 4). The synthesis and taste-enhancingactivity of compound 80 were reported by Ottinger et al.213

(Table 16, entry 5). The enantiomer (+)-(S)-80 was found tobe the physiologically active one, whereas (-)-(R)-80 did notaffect sweetness perception at all. Racemization was observedduring the synthesis of betaine (+)-(S)-80 by reaction be-tween HMF and L-alanine under alkaline conditions, resultingin lower taste-enhancing activity. Villard et al.152 (Table 16,entry 6) reported an alternative two step synthetic protocolfor the preparation of enantiopure final products although inlower yields. Soldo and Hofmann extended these investigationsby the synthesis and screening of the bitterness-suppressingproperties of pyridinium betaines 81a–c 214 (Table 16,entry 7).

5.6 Synthesis of heteromacrocycles

The hydroxyl and aldehyde functional groups present in HMFare appealing structural motifs for the synthesis of heteromacro-cycles, which are of considerable interest due to their biologicalactivity and complexation properties.

Heteromacrocyclic compounds 84 and 85 were preparedfrom 2,5-disubstituted furans 82 and 83 via ring-closingmetathesis (RCM) catalyzed by commercially available benzyli-dene bis(tricyclohexylphosphine)ruthenium dichloride (Grubbscatalyst).147a The formation of 84 instead of 86 was explained bythe authors as due to possible conformational constraints in theoriginal substrate (Scheme 71).

Another attempt to obtain 86 in two steps from HMF chloroalcohol 87 was also unsuccessful, the macrocycle 84 again beingthe only product formed (35% yield) (Scheme 72).

Heteromacrocycles 88–91 were obtained starting fromHMF in low to moderate yields.217 These kind of com-pounds are themselves hosts for binding organic and


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Table 16 Examples on the transformation of HMF to 2-hydroxymethyl-pyridinium derivatives

Entry (ref.) Starting compound Reaction conditions Product Yield (%)

1215 HMF MeNH2, EtOH–H2O 10a

2153b Br2, H2O, 0 ◦C 78b

3215a,216 HMF 1-Propylamine, H2O–EtOH, NaOH, pH 9.4,reflux, 3 days.

43–45

4215 HMF N-Acetyllysine, EtOH, NaOH —

5213 HMF Alanine, NaOH, H2O–EtOH, pH 9.4, reflux, 48 h 51

6152 HMF (1) L- or D-Alanine, water, aq. NaOH (32%), pH8.5, Ni, H2, RT, 5 bar, 48 h; (2) water, 0 ◦C,Br2–MeOH (0.5 h), RT (1 h)

13b

7214 HMF Glycine, b-alanine, or g-aminobutyric acid,H2O–EtOH, NaOH, pH 9.4, RT (1.5 h), reflux(24 h)

22 (81a),12 (81b),5 (81c)

a Pachmayr et al.215b reported 10% in the presence of AcOH while Koch et al.215a used HMF with aq. MeNH2 for 3 days under reflux and used thecrude product directly for further transformation. b Yield from the second step.

inorganic cations. More importantly, they can serve asstarting materials for preparing host compounds whose pe-riphery is lined with a variety of binding and shaping units(Scheme 73).

Waddell et al.218 developed a method for the synthe-sis of heteromacrocyclic derivatives of HMF, 93 and 94,which have the same substituents on the ‘eastern’ side asthe erythromycin-derived azalide antibiotics 9-deoxo-9a-aza-9a-methyl-8a-homoerythromycin A and 9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A, but more functionalized ‘west-ern’ sides, due to the introduction of a tetrahydrofuran ringderived from HMF. Compounds 93 and 94 were prepared inseveral steps from erythromycin-derived acyclic fragment 92and HMF protected as its 5-tert-butyldimethylsilyl ether, 4a(Scheme 74).

A macrocyclic fluorescent receptor 95 was synthesised fromHMF, and binding studies with three different types of dicar-boxylic acids were performed147d (Scheme 75).

6 Conclusions

Recently, considerable efforts have been made in order toachieve more efficient integrated processes for the transforma-tion of carbohydrates into HMF. Considerable improvementhas been reported for the conversion of fructose to HMF,whereas the transformation of glucose, sucrose and celluloseremains difficult. The main drawback for the transformation ofglucose-based carbohydrates to HMF is the isomerisation tofructose, which requires different conditions from the fructosedehydration step. As a result, an overall process based on


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


Scheme 71

Scheme 72

two independent steps is more desirable, and has been alreadyexplored by combining base/acid66 or enzyme/acid80 catalyticsystems. More efficient reaction conditions (lower temperature,and higher carbohydrate initial concentration), higher conver-sions and HMF selectivity are desirable, and these processeshave to be environmentally friendly.

The presence of two functional groups in HMF, combinedwith the furan ring, makes it an appealing starting materialfor various chemical transformations. Several transformationsof HMF as a substrate involving formyl or hydroxyl groups(or both) have been reported in the literature. Serious attentionwas paid to the oxidation and reduction, because they provideconvenient synthetic pathways for the production of chemicalbuilding blocks for the polymer industry and biofuels startingfrom renewable materials. Heterogeneous metal catalysts and airas the oxidant is the modern approach for performing selectiveoxidation of HMF and synthesis of FDA and DFF. A lot ofresearch in this direction has already been done, and some reallygood results have been achieved for the oxidation of HMF toFDA in water – an economical and environmentally friendlysolvent. Nevertheless, considerable amounts of base (and high

Scheme 73

Scheme 74

Scheme 75

temperatures) are required for this transformation, and futureinvestigations will focus on the resolution of these issues. Ionicliquids seem to be a promising medium for the oxidation, butthere are still few examples of their application, especially forthe synthesis of DFF.

The conversion of 2,5-bis(hydroxymethyl)furan (which isalready in use for the production of polyurethane foams)to 2,5-dimethylfuran (a compound of considerable interest


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


because of its potential as biofuel and fuel additive) has beencarried out by hydrogenolysis. Very good results have beenreported for the synthesis of 2,5-bis(hydroxymethyl)furan byhydrogenolysis promoted by Pt, while the reduction of HMFto 2,5-dimethylfuran has resulted in low to moderate yieldsand selectivity. Screening of more effective catalysts for thistransformation needs to be considered.

Some catalysts were found to be effective for the transfor-mations of not only neat HMF, but also crude HMF resultingfrom the dehydration of carbohydrates. This approach leads toreduced reaction costs, and it is important for industry that thesearch for new catalysts leading to high yields and selectivitycontinues.

In view of the reported data, many questions about HMFand its derivative product(s) remain to be answered. There area number of reports that do not agree about the toxicology ofthis compound to humans, and therefore more experimentalwork needs to be developed – for instance, in the study of thetoxicology of derivatives of HMF. As far as its effect on thewider environment is concerned, it is probably not a problem,because HMF is mainly produced during food processing andfrom there proceeds directly to the human food chain, so itis unlikely to enter in the environment in amounts to causeconcern. The only exception might be in the case of industrialsynthesis of HMF, using natural resources (or otherwise), as wellas its derivatization to form new important molecules, includingbiofuels. Experimental studies should be carried out in orderto ascertain that such processes will not generate toxic wasteproducts. Biodegradability studies of HMF derivatives shouldbe performed in order to investigate how much greener this newsource of energy would be if applied on a large scale. The useof lignocelluloses for biofuel production would be of particularimportance, since this is a cheap and readily available naturalsource that would decrease the amounts of petroleum-derivedpollutants in the air, thus contributing to a greener environment.

7 Acknowledgements

We thank the Fundacao para a Ciencia e Tecnologia(POCI 2010) and FEDER (Ref.:SFRH/BD/28242/2006,PTDC/QUI/66695/2006, PTDC/QUI/73061/2006,PTDC/QUI/71331/2006) for financial support.

8 References1 B. Kamm, Angew. Chem., Int. Ed., 2007, 46, 5056–5058.2 D. Brownlie, J. Soc. Chem. Ind., 1940, 59, 671–675.3 (a) A. Corma, S. Iborra and A. Velty, Chem. Rev., 2007, 107, 2411–

2502; (b) C. H. Christensen, J. Rass-Hansen, C. C. Marsden, E.Taarning and K. Egeblad, ChemSusChem, 2008, 1, 283–289.

4 J. F. Saeman, Ind. Eng. Chem., 1945, 37, 43–52.5 G. Dull, Chem. Ztg., 1895, 216.6 J. Kiermayer, Chem. Ztg., 1895, 19, 1003.7 (a) H. J. H. Fenton and M. Gostling, J. Chem. Soc., 1901, 79, 807–

816; (b) H. J. H. Fenton and F. Robinson, J. Chem. Soc., 1909, 95,1334–1340; (c) T. Reichstein, Helv. Chim. Acta, 1926, 9, 1066–1068;(d) T. Reichstein and H. Zschokke, Helv. Chim. Acta, 1932, 15, 249–253; (e) W. N. Haworth and W. G. M. Jones, J. Chem. Soc., 1944,667–670.

8 F. H. Newth, Adv. Carbohydr. Chem., 1951, 6, 83–106.9 C. J. Moye and Z. S. Krzeminski, Aust. J. Chem., 1963, 16, 258.

10 M. S. Feather and J. F. Harris, in Dehydration Reactions ofCarbohydrates, ed. R. S. Tipson and H. Derek, Academic Press,1973.

11 A. Gaset, J. P. Gorrichon and E. Truchot, Inf. Chim., 1981, 212,179.

12 A. Faury, A. Gaset and J. P. Gorrichon, Inf. Chim., 1981, 214, 203.13 B. F. M. Kuster, Starch/Staerke, 1990, 42, 314–321.14 L. Cottier and G. Descotes, Trends Heterocycl. Chem., 1991, 2, 233.15 J. Lewkowski, Arkivoc, 2001, 2, 17–54.16 C. Moreau, M. N. Belgacem and A. Gandini, Top. Catal., 2004, 27,

11–30.17 A. Boisen, T. B. Christensen, W. Fu, Y. Y. Gorbanev, T. S. Hansen,

J. S. Jensen, S. K. Klitgaard, S. Pedersen, A. Riisager, T. Stahlbergand J. M. Woodley, Chem. Eng. Res. Des., 2009, 87, 1318–1327.

18 Y. G. Zhang and J. Y. G. Chan, Energy Environ. Sci., 2010, 3, 408–417.

19 (a) F. W. Lichtenthaler and S. Peters, C. R. Chim., 2004, 7, 65–90;(b) X. L. Tong, Y. Ma and Y. D. Li, Appl. Catal., A, 2010, 385, 1–13;(c) A. Gandini, Polym. Chem., 2010, 1, 245–251; (d) R. J. Ulbricht,S. J. Northup and J. A. Thomas, Fundam. Appl. Toxicol., 1984, 4,843–853.

20 Search made in ISI Web of Knowledge with topic ‘5-hydroxymethylfurfural’.

21 L. W. Kroh, Food Chem., 1994, 51, 341–416.22 H. F. Erbersdobler and A. Hupe, Z. Ernaehrungswiss., 1991, 30,

46–49.23 (a) H. E. Berg and M. A. J. S. Van Boekel, Netherlands Milk Dairy

J., 1994, 48, 157–175; (b) C. Martin and L. J. Jonsson, EnzymeMicrob. Technol., 2003, 32, 386–395.

24 F. J. Morales, C. Romero and S. Jimenez-Perez, J. Agric. Food Chem.,1997, 45, 1570.

25 (a) A. Ramirez-Jimenez, E. Guerra-Hernandez and B. Garcia-Villanova, J. Agric. Food Chem., 2000, 48, 4176–4181; (b) L. A.Ameur, G. Trystram and I. Birlouez-aragon, Food Chem., 2005, 98,790–796.

26 (a) P. Fernandez-Artigas, E. Guerra-Hernandez and B. Garcia-Villanova, J. Agric. Food Chem., 1999, 47, 2872–2878; (b) A.Ramırez-Jimenez, B. Garcıa-Villanova and E. Guerra-Hernandez,Food Res. Int., 2000, 33, 833–838; (c) A. Ramirez-Jimenez, B.Garcıa-Villanova and E. Guerra-Hernandez, J. Sci. Food Agric.,2001, 81, 513–518; (d) J. A. Rufian-Henares, C. Delgado-Andradeand F. J. Morales, J. Cereal Sci., 2006, 43, 63–69.

27 B. Fallico, E. Arena and M. Zappala, Food Chem., 2003, 81, 569–573.

28 L. Ait Ameur, O. Mathieu, V. Lalanne, G. Trystram and I. Birlouez-Aragon, Food Chem., 2007, 101, 1407–1416.

29 M. J. Taherzadeh, L. Gustafsson, C. Niklasson and G. Liden, Appl.Microbiol. Biotechnol., 2000, 53, 701–708.

30 C. F. Wahlbom and B. Hahn-Hagerdal, Biotechnol. Bioeng., 2001,78, 172–178.

31 Z. L. Liu, P. J. Slininger, B. S. Dien, M. A. Berhow, C. P. Kurtzmanand S. W. Gorsich, J. Ind. Microbiol. Biotechnol., 2004, 31, 345–352.

32 P. J. Slininger, S. W. Gorsich and Z. L. Liu, Biotechnol. Bioeng.,2009, 102, 778–790.

33 C. Hu, X. Zhao, J. Zhao, S. Wu and Z. K. Zhao, Bioresour. Technol.,2009, 100, 4843–4847.

34 J. Zaldivar, A. Martinez and L. O. Ingram, Biotechnol. Bioeng.,1999, 65, 24–33.

35 X. Chen, Z. H. Li, X. X. Zhang, F. X. Hu, D. D. Y. Ryu and J. Bao,Appl. Biochem. Biotechnol., 2009, 159, 591–604.

36 (a) M. Murkovic and N. Pichler, Mol. Nutr. Food Res., 2006, 50,842–846; (b) R. L. Prior, X. Wu and L. Gu, J. Agric. Food Chem.,2006, 54, 3744–3749.

37 T. Husoy, M. Haugen, M. Murkovic, D. Jobstl, L. H. Stolen, T.Bjellaas, C. Ronningborg, H. Glatt and J. Alexander, Food Chem.Toxicol., 2008, 46, 3697–3702.

38 (a) C. L. Hryncewicz, M. Koberda and M. S. Konkowski, J. Pharm.Biomed. Anal., 1996, 14, 429–434; (b) E. Jellum, H. C. Borresen andL. Eldjarn, Clin. Chim. Acta, 1973, 47, 191–201; (c) A. P. Wieslander,A. H. Andren, C. Nilsson-Thorell, N. Muscalu, P. T. Kjellstrand andB. Rippe, Peritoneal Dialysis Int., 1995, 15, 348–352.

39 C. Janzowski, V. Glaab, E. Samimi, J. Schlatter and G. Eisenbrand,Food Chem. Toxicol., 2000, 38, 801–809.

40 (a) I. Severin, C. Dumont, A. Jondeau-Cabaton, V. Graillot and M.C. Chagnon, Toxicol. Lett., 2010, 192, 189–194; (b) K. H. Wagner,S. Reichhold, K. Koschutnig, S. Cheriot and C. Billaud, Mol. Nutr.Food Res., 2007, 51, 496–504.


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


41 C. M. Brands, G. M. Alink, M. A. van Boekel and W. M. Jongen,J. Agric. Food Chem., 2000, 48, 2271–2275.

42 X. Ding, M. Y. Wang, Y. X. Yao, G. Y. Li and B. C. Cai, J.Ethnopharmacol., 2010, 128, 373–376.

43 A. S. Lin, K. Qian, Y. Usami, L. Lin, H. Itokawa, C. Hsu, S. L.Morris-Natschke and K. H. Lee, J. Nat. Med., 2008, 62, 164–167.

44 O. Abdulmalik, M. K. Safo, Q. Chen, J. Yang, C. Brugnara, K.Ohene-Frempong, D. J. Abraham and T. Asakura, Br. J. Haematol.,2005, 128, 552–561.

45 L. J. Durling, L. Busk and B. E. Hellman, Food Chem. Toxicol.,2009, 47, 880–884.

46 H. Glatt, H. Schneider and Y. Liu, Mutat. Res., 2005, 580, 41–52.47 P. Khondkar, M. M. Rahman and A. Islam, Phytother. Res., 2005,

19, 816–817.48 X. M. Zhang, C. C. Chan, D. Stamp, S. Minkin, M. C. Archer and

W. R. Bruce, Carcinogenesis, 1993, 14, 773–775.49 Y. J. Surh, A. Liem, J. A. Miller and S. R. Tannenbaum, Carcino-

genesis, 1994, 15, 2375–2377.50 W. Teubner, W. Meinl, S. Florian, M. Kretzschmar and H. Glatt,

Biochem. J., 2007, 404, 207–215.51 Y. C. Lee, M. Shlyankevich, H. K. Jeong, J. S. Douglas and Y. J.

Surh, Biochem. Biophys. Res. Commun., 1995, 209, 996–1002.52 B. H. Monien, H. Frank, A. Seidel and H. Glattt, Chem. Res.

Toxicol., 2009, 22, 1123–1128.53 N. Bakhiya, B. Monien, H. Frank, A. Seidel and H. Glatt, Biochem.

Pharmacol., 2009, 78, 414–419.54 V. B. Godfrey, L. J. Chen, R. J. Griffin, E. H. Lebetkin and L. T.

Burka, J. Toxicol. Environ. Health, Part A, 1999, 57, 199–210.55 C. Svendsen, T. Husoy, H. Glatt, J. E. Paulsen and J. Alexander,

Anticancer Res., 2009, 29, 1921–1926.56 M. J. Antal, W. S. L. Mok and G. N. Richards, Carbohydr. Res.,

1990, 199, 91–109.57 H. E. Vandam, A. P. G. Kieboom and H. Vanbekkum,

Starch/Staerke, 1986, 38, 95–101.58 A. Cukalovic and C. V. Stevens, Green Chem., 2010, 12, 1201–1206.59 C. Moreau, R. Durand, S. Razigade, J. Duhamet, P. Faugeras, P.

Rivalier, P. Ros and G. Avignon, Appl. Catal., A, 1996, 145, 211–224.60 (a) S. Lima, P. Neves, M. M. Antunes, M. Pillinger, N. Ignatyev

and A. A. Valente, Appl. Catal., A, 2009, 363, 93–99; (b) Y. Roman-Leshkov, C. J. Barrett, Z. Y. Liu and J. A. Dumesic, Nature, 2007,447, 982 -U985; (c) J. N. Chheda, Y. Roman-Leshkov and J. A.Dumesic, Green Chem., 2007, 9, 342–350; (d) Y. Roman-Leshkov, J.N. Chheda and J. A. Dumesic, Science, 2006, 312, 1933–1937; (e) F.Benvenuti, C. Carlini, P. Patrono, A. M. R. Galletti, G. Sbrana, M.A. Massucci and P. Galli, Appl. Catal., A, 2000, 193, 147–153.

61 (a) S. Q. Hu, Z. F. Zhang, Y. X. Zhou, B. X. Han, H. L. Fan, W.J. Li, J. L. Song and Y. Xie, Green Chem., 2008, 10, 1280–1283;(b) S. Q. Hu, Z. F. Zhang, J. L. Song, Y. X. Zhou and B. X. Han,Green Chem., 2009, 11, 1746–1749; (c) S. Q. Hu, Z. F. Zhang, Y. X.Zhou, J. L. Song, H. L. Fan and B. X. Han, Green Chem., 2009, 11,873–877; (d) M. Chidambaram and A. Bell, Green Chem., 2010, 12,1253–1262.

62 J. Y. G. Chan and Y. G. Zhang, ChemSusChem, 2009, 2, 731–734.63 H. P. Yan, Y. Yang, D. M. Tong, X. Xiang and C. W. Hu, Catal.

Commun., 2009, 10, 1558–1563.64 Y. T. Zhang, H. B. Du, X. H. Qian and E. Y. X. Chen, Energy Fuels,

2010, 24, 2410–2417.65 (a) R. M. Musau and R. M. Munavu, Biomass, 1987, 13, 67–74;

(b) M. L. Ribeiro and U. Schuchardt, Catal. Commun., 2003, 4,83–86; (c) X. H. Qi, M. Watanabe, T. M. Aida and R. L. Smith, Ind.Eng. Chem. Res., 2008, 47, 9234–9239.

66 A. Takagaki, M. Ohara, S. Nishimura and K. Ebitani, Chem.Commun., 2009, 6276–6278.

67 D. W. Brown, A. J. Floyd, R. G. Kinsman and Y. Roshanali, J.Chem. Technol. Biotechnol., 1982, 32, 920–924.

68 C. Moreau, A. Finiels and L. Vanoye, J. Mol. Catal. A: Chem.,2006, 253, 165–169.

69 B. F. M. Kuster and J. Laurens, Starch/Staerke, 1977, 29, 172–176.

70 J. D. Chen, B. F. M. Kuster and K. Vanderwiele, Biomass Bioenergy,1991, 1, 217–223.

71 T. S. Hansen, J. M. Woodley and A. Riisager, Carbohydr. Res., 2009,344, 2568–2572.

72 C. Sievers, I. Musin, T. Marzialetti, M. B. V. Olarte, P. K. Agrawaland C. W. Jones, ChemSusChem, 2009, 2, 665–671.

73 (a) X. H. Qi, M. Watanabe, T. M. Aida and R. L. Smith,ChemSusChem, 2009, 2, 944–946; (b) X. H. Qi, M. Watanabe, T.M. Aida and R. L. Smith, Green Chem., 2009, 11, 1327–1331.

74 D. M. Roberge, L. Ducry, N. Bieler, P. Cretton and B. Zimmermann,Chem. Eng. Technol., 2005, 28, 318–323.

75 T. Tuercke, S. Panic and S. Loebbecke, Chem. Eng. Technol., 2009,32, 1815–1822.

76 F. Ilgen, D. Ott, D. Kralisch, C. Reil, A. Palmberger and B. Konig,Green Chem., 2009, 11, 1948–1954.

77 T. M. Aida, Y. Sato, M. Watanabe, K. Tajima, T. Nonaka, H. Hattoriand K. Arai, J. Supercrit. Fluids, 2007, 40, 381–388.

78 Y. Roman-Leshkov and J. A. Dumesic, Top. Catal., 2009, 52, 297–303.

79 H. B. Zhao, J. E. Holladay, H. Brown and Z. C. Zhang, Science,2007, 316, 1597–1600.

80 R. L. Huang, W. Qi, R. X. Su and Z. M. He, Chem. Commun., 2010,46, 1115–1117.

81 M. Y. Chernyak, M. A. Smirnova and V. E. Tarabanko, RU2363698-C1, 2009.

82 S. Wu, H. Fan, Y. Xie, Y. Cheng, Q. Wang, Z. Zhang and B. Han,Green Chem., 2010, 12, 1215–1219.

83 F. S. Asghari and H. Yoshida, Ind. Eng. Chem. Res., 2006, 45, 2163–2173.

84 M. Bicker, J. Hirth and H. Vogel, Green Chem., 2003, 5, 280–284.85 M. Bicker, D. Kaiser, L. Ott and H. Vogel, J. Supercrit. Fluids, 2005,

36, 118–126.86 P. Vinke and H. Vanbekkum, Starch/Staerke, 1992, 44, 90–96.87 (a) C. Lansalot-Matras and C. Moreau, Catal. Commun., 2003, 4,

517–520; (b) G. A. Halliday, R. J. Young and V. V. Grushin, Org.Lett., 2003, 5, 2003–2005.

88 K. Shimizu, R. Uozumi and A. Satsuma, Catal. Commun., 2009,10, 1849–1853.

89 J. N. Chheda and J. A. Dumesic, Catal. Today, 2007, 123, 59–70.90 X. H. Qi, M. Watanabe, T. M. Aida and R. L. Smith, Green Chem.,

2008, 10, 799–805.91 A. S. Amarasekara, L. D. Williams and C. C. Ebede, Carbohydr.

Res., 2008, 343, 3021–3024.92 S. Murugesan and R. J. Linhardt, Curr. Org. Synth., 2005, 2, 437–

451.93 (a) Q. B. Liu, M. H. A. Janssen, F. van Rantwijk and R. A. Sheldon,

Green Chem., 2005, 7, 39–42; (b) A. A. Rosatella, L. C. Branco andC. A. M. Afonso, Green Chem., 2009, 11, 1406–1413.

94 Q. X. Bao, K. Qiao, D. Tomida and C. Yokoyama, Catal. Commun.,2008, 9, 1383–1388.

95 C. Fayet and J. Gelas, Carbohydr. Res., 1983, 122, 59–68.96 (a) J. Lifka, B. Ondruschka and A. Stark, DE102008009933-A1,

DE102008009933-A1, 2009; C07D-307/50 200956; (b) J. Lifka, B.Ondruschka and A. Stark, DE102008009933-A1, 2009.

97 H. Zhao, J. E. Holladay and Z. C. Zhang, US2008033187-A1;WO2008019219-A1; EP2054400-A1, 2008.

98 G. Yong, Y. G. Zhang and J. Y. Ying, Angew. Chem., Int. Ed., 2008,47, 9345–9348.

99 C. Z. Li, Z. H. Zhang and Z. B. K. Zhao, Tetrahedron Lett., 2009,50, 5403–5405.

100 Z. H. Zhang and Z. B. K. Zhao, Bioresour. Technol., 2010, 101,1111–1114.

101 S. Yu, H. M. Brown, X. W. Huang, X. D. Zhou, J. E. Amonette andZ. C. Zhang, Appl. Catal., A, 2009, 361, 117–122.

102 J. A. Chun, J. W. Lee, Y. B. Yi, S. S. Hong and C. H. Chung, KoreanJ. Chem. Eng., 2010, 27, 930–935.

103 J. B. Binder and R. T. Raines, J. Am. Chem. Soc., 2009, 131, 1979–1985.

104 (a) J. B. Binder and R. T. Raines, WO2009155297-A1;US2010004437-A1; (b) J. B. Binder and R. T. Raines,WO2009155297-A1; US2010004437-A1, 2009.

105 E. A. Pidko, V. Degirmenci, R. A. van Santen and E. J. M. Hensen,Angew. Chem., Int. Ed., 2010, 49, 2530–2534.

106 M. Watanabe, Y. Aizawa, T. Iida, T. M. Aida, C. Levy, K. Sue andH. Inomata, Carbohydr. Res., 2005, 340, 1925–1930.

107 X. H. Qi, M. Watanabe, T. M. Aida and R. L. Smith, Catal.Commun., 2008, 9, 2244–2249.

108 X. H. Qi, M. Watanabe, T. M. Aida and R. L. Smith, Catal.Commun., 2009, 10, 1771–1775.

109 A. Chareonlimkun, V. Champreda, A. Shotipruk and N.Laosiripojana, Bioresour. Technol., 2010, 101, 4179–4186.


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


110 F. S. Asghari and H. Yoshida, Carbohydr. Res., 2006, 341, 2379–2387.

111 (a) H. Ishida and K.-i. Seri, J. Mol. Catal. A: Chem., 1996, 112,L163–L165; (b) K. Seri, Y. Inoue and H. Ishida, Bull. Chem. Soc.Jpn., 2001, 74, 1145–1150.

112 T. Stahlberg, M. G. Sorensen and A. Riisager, Green Chem., 2010,12, 321–325.

113 (a) C. Carlini, M. Giuttari, A. M. R. Galletti, G. Sbrana, T. Armaroliand G. Busca, Appl. Catal., A, 1999, 183, 295–302; (b) T. Armaroli,G. Busca, C. Carlini, M. Giuttari, A. M. R. Galletti and G. Sbrana,J. Mol. Catal. A: Chem., 2000, 151, 233–243.

114 M. Hara, K. Nakajima and S. Yamashita, JP2009215172-A, 2009.115 C. Carlini, P. Patrono, A. M. R. Galletti and G. Sbrana, Appl. Catal.,

A, 2004, 275, 111–118.116 T. Werpy and G. Petersen, Top Value Added Chemicals from Biomass,

US Dept. of Energy, 2004, vol. 1, pp. 26–28.117 T. Elhajj, A. Masroua, J. C. Martin and G. Descotes, Bull. Soc.

Chim. Fr., 1987, 855–860.118 B. W. Lew, U. S. Pat. 3326944, Chem. Abstr., 1968, 68, P49434n.119 Y. Y. Gorbanev, S. K. Klitgaard, J. M. Woodley, C. H. Christensen

and A. Riisager, ChemSusChem, 2009, 2, 672–675.120 O. Casanova, S. Iborra and A. Corma, ChemSusChem, 2009, 2,

1138–1144.121 S. E. Davis, L. R. Houkb, E. C. Tamargoa, A. K. Datyeb and R. J.

Davis, Catal. Today, 2010, DOI: 10.1016/j.cattod.2010.1006.1004.122 M. P. J. vanDeurzen, F. vanRantwijk and R. A. Sheldon, J.

Carbohydr. Chem., 1997, 16, 299–309.123 A. Gandini and M. N. Belgacem, Prog. Polym. Sci., 1997, 22, 1203–

1379.124 L. Cottier, G. Descotes, J. Lewkowski, R. Skowronski and E. Viollet,

J. Heterocycl. Chem., 1995, 32, 927–930.125 J. W. Van Reijendam, G. J. Heeres and M. J. Janssen, Tetrahedron,

1970, 26, 1291.126 S. Morikawa, Noguchi Kenkyusho Jiho, 1978, 21, 25; S. Morikawa,

Chem. Abstr., 1979, 90, 103740d.127 E. L. Clennan and M. E. Mehrsheikh-Mohammadi, J. Am. Chem.

Soc., 1984, 106, 7112–7118.128 S. Morikawa, Noguchi Kenkyusho Jiho, 1979, 22, 20; S. Morikawa,

Chem. Abstr., 1980, 90, 198181a.129 L. Cottier, G. Descotes, J. Lewkowski and R. Skowronski, Org. Prep.

Proced. Int., 1995, 27, 564–566.130 L. Cottier, G. Descotes, J. Lewkowski and R. Skowronski, Pol. J.

Chem., 1994, 68, 693–698.131 P. J. McDermott and R. A. Stockman, Org. Lett., 2005, 7, 27–29.132 H. Mehdi, A. Bodor, D. Lantos, I. T. Horvath, D. E. De Vos and

K. Binnemans, J. Org. Chem., 2007, 72, 517–524.133 R. Davies, U. Hedebrant, I. Athanassiadis, P. Rydberg and M.

Tornqvist, Food Chem. Toxicol., 2009, 47, 1950–1957.134 W. Partenheimer and V. V. Grushin, Adv. Synth. Catal., 2001, 343,

102–111.135 C. Carlini, P. Patrono, A. M. R. Galletti, G. Sbrana and V. Zima,

Appl. Catal., A, 2005, 289, 197–204.136 A. S. Amarasekara, D. Green and E. McMillan, Catal. Commun.,

2008, 9, 286–288.137 O. C. Navarro, A. C. Canos and S. I. Chornet, Top. Catal., 2009,

52, 304–314.138 M. A. Lilga, R. T. Hallen, J. Hu, J. F. White and M. J. Gray,

US2008103318-A1, 2007.139 M. A. Lilga, R. T. Hallen and M. Gray, Top. Catal., 2010, 53,

1264–1269.140 R. Skowronski, L. Cottier, G. Descotes and J. Lewkowski, Synthesis,

1996, 1291–1292.141 L. Cottier, G. Descotes and J. Lewkowski, Synth. Commun., 1994,

24, 939–944.142 P. Vinke, W. van der Poel and H. v. Bekkum, Stud. Surf. Sci. Catal.,

1991, 59.143 E. Taarning, I. S. Nielsen, K. Egeblad, R. Madsen and C. H.

Christensen, ChemSusChem, 2008, 1, 75–78.144 O. Casanova, S. Iborra and A. Corma, J. Catal., 2009, 265, 109–

116.145 (a) L. Cottier, G. Descotes, H. Nigay, J. C. Parron and V. Gregoire,

Bull. Soc. Chim. Fr., 1986, 844–850; (b) R. Alibes, J. Font, A. Mulaand R. M. Ortuno, Synth. Commun., 1990, 20, 2607–2615; (c) L.Cottier, G. Descotes, L. Eymard and K. Rapp, Synthesis, 1995,303–306.

146 C. Marisa, D. Ilaria, R. Marotta, A. Roberto and C. Vincenzo, J.Photochem. Photobiol., A, 2010, 210, 69–76.

147 (a) L. Cottier, G. R. Descotes and Y. Soro, Synth. Commun., 2003,33, 4285–4295; (b) C. J. Moye, Pure. Appl. Chem., 1964, 14, 161;(c) J. M. Timko and D. J. Cram, J. Am. Chem. Soc., 1974, 96, 7159–7160; (d) S. Goswami, S. Dey and S. Jana, Tetrahedron, 2008, 64,6358–6363; (e) F. W. Lichtenthaler, A. Brust and E. Cuny, GreenChem., 2001, 3, 201–209.

148 J. H. Turner, P. A. Rebers, P. L. Barrick and R. H. Cotton, Anal.Chem., 1954, 26, 898–901.

149 V. Schiavo, G. Descotes and J. Mentech, Bull. Soc. Chim. Fr., 1991,704–711.

150 (a) W. N. Haworth, W. G. M. Jones and L. F. Wiggins, J. Chem.Soc., 1945, 1–4; (b) A. C. Cope and W. N. Baxter, J. Am. Chem.Soc., 1955, 77, 393–396.

151 G. C. A. Luijkx, N. P. M. Huck, F. van Rantwijk, L. Maat and H.van Bekkum, Heterocycles, 2009, 77, 1037–1044.

152 R. Villard, F. Robert, I. Blank, G. Bernardinelli, T. Soldo and T.Hofmann, J. Agric. Food Chem., 2003, 51, 4040–4045.

153 (a) N. Elming and N. Clausonkaas, Acta Chem. Scand., 1956,10, 1603–1605; (b) C. Muller, V. Diehl and F. W. Lichtenthaler,Tetrahedron, 1998, 54, 10703–10712.

154 K. Kojiri, H. Kondo, H. Arakawa, M. Ohkubo and H. Suda,US6703373-B1.

155 S. G. Sun and W. V. Murray, J. Org. Chem., 1999, 64, 5941–5945.156 T. Fumagalli, G. Sello and F. Orsini, Synth. Commun., 2009, 39,

2178–2195.157 Z. Mouloungui, M. Delmas and A. Gaset, Synth. Commun., 1984,

14, 701–705.158 S. N. Goodman and E. N. Jacobsen, Adv. Synth. Catal., 2002, 344,

953–956.159 N. Almirante, A. Cerri, G. Fedrizzi, G. Marazzi and M. San-

tagostino, Tetrahedron Lett., 1998, 39, 3287–3290.160 (a) C. Z. Yu, B. Liu and L. Q. Hu, J. Org. Chem., 2001, 66, 5413–

5418; (b) C. Z. Yu and L. Q. Hu, J. Org. Chem., 2002, 67, 219–223.

161 L. Cottier, G. Descotes and Y. Soro, J. Carbohydr. Chem., 2005, 24,55–71.

162 I. Terada, T. Takeda, T. Kobayashi, T. Hiramoto and K.Tsuyoshi, US2010029786-A1 WO2008044784-A1, 2008; C07D-307/00 200863, 2008.

163 T. Urashima, K. Suyama and S. Adachi, Carbohydr. Res., 1985, 135,324–329.

164 J. A. Dumesis, G. W. Huber, J. N. Chheda, C. J. Bar-rett and J. A. Dumesic, WO2007103858-A2; WO2007103858-A3; US2008058563-A1; US7671246-B2, WO2007103858-A2, 2007;C07C-001/00 200821.

165 R. Skowronski, G. Grabowski, J. Lewkowski, G. Descotes, L.Cottier and C. Neyret, Org. Prep. Proced. Int., 1993, 25, 353–355.

166 H. Quiroz-Florentino, R. Aguilar, B. M. Santoyo, F. Diaz and J.Tamariz, Synthesis, 2008, 1023–1028.

167 W. Hanefeld, M. Schlitzer, N. Debski and H. Euler, J. Heterocycl.Chem., 1996, 33, 1143–1146.

168 N. Shinobu, J. Shao, M. Kobayashi, T. Mori, K. Masataka, S.Noriaki and M. Takao, WO2008056634-A1; CN101535302-A; EP2130829-A1; JP2008543069-X; US2010076049-A1,WO2008056634-A1, 2008; C07D-405/00 200867.

169 S. N. Suryawanshi, N. Chandra, P. Kumar, J. Porwal and S. Gupta,Eur. J. Med. Chem., 2008, 43, 2473–2478.

170 R. T. Cummings, J. P. Dizio and G. A. Krafft, Tetrahedron Lett.,1988, 29, 69–72.

171 L. Lin, Q. Shi, A. K. Nyarko, K. F. Bastow, C. C. Wu, C. Y. Su, C.C. Y. Shih and K. H. Lee, J. Med. Chem., 2006, 49, 3963–3972.

172 (a) A. Muther and B. Tollens, Ber. Dtsch. Chem. Ges., 1904, 37, 306–311; (b) A. Wahhab, J. Am. Chem. Soc., 1948, 70, 3580–3582; (c) W.Volksen, Arch. Pharm. Ber. Dtsch. Pharm. Ges., 1954, 287, 459–462;(d) H. Kato, Bull. Agric. Chem. Soc. Jpn., 1959, 23, 551–554; (e) K.Michail, V. Matzi, A. Maier, R. Herwig, J. Greilberger, H. Juan,O. Kunert and R. Wintersteiger, Anal. Bioanal. Chem., 2007, 387,2801–2814.

173 E. Erdmann, Ber. Dtsch. Chem. Ges., 1910, 43, 2391–2398.174 E. Erdmann and C. Schaefer, Ber. Dtsch. Chem. Ges., 1910, 43,

2398–2406.175 T. S. Gardner, F. A. Smith, E. Wenis and J. Lee, J. Org. Chem., 1951,

16, 1121–1125.


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


176 W. F. Cooper and W. H. Nuttall, J. Chem. Soc., 1912, 101, 1074–1081.

177 G. Kallinich, Arch. Pharm. Ber. Dtsch. Pharm. Ges., 1958, 291/63,274–277.

178 A. S. Amarasekara, O. Edigin and W. Hernandez, Lett. Org. Chem.,2007, 4, 306–308.

179 F. Liu, A. G. Stephen, R. J. Fisher and T. R. Burke Jr., Bioorg. Med.Chem. Lett., 2008, 18, 1096–1101.

180 K. Undheim, J. Roe and T. Greibrok, Acta Chem. Scand., 1969, 23,2501.

181 L. Sattler, F. W. Zerban, G. L. Clark and C. C. Chu, J. Am. Chem.Soc., 1951, 73, 5908–5910.

182 X. Shao, Z. Li, X. Qian and X. Xu, J. Agric. Food Chem., 2009, 57,951–957.

183 I. M. Karaguni, K. H. Glusenkamp, A. Langerak, C. Geisen, V.Ullrich, G. Winde, T. Moroy and O. Muller, Bioorg. Med. Chem.Lett., 2002, 12, 709–713.

184 J. J. Matasi, J. P. Caldwell, J. Hao, B. Neustadt, L. Arik, C. J. Foster,J. Lachowicz and D. B. Tulshian, Bioorg. Med. Chem. Lett., 2005,15, 1333–1336.

185 R. Miller, Acta Chem. Scand., Ser. B, 1987, 41, 208–209.186 A. Baliani, G. J. Bueno, M. L. Stewart, V. Yardley, R. Brun, M. P.

Barrett and I. H. Gilbert, J. Med. Chem., 2005, 48, 5570–5579.187 J. Ramonczai and L. Vargha, J. Am. Chem. Soc., 1950, 72, 2737–

2737.188 G. Papadogianakis, L. Maat and R. A. Sheldon, J. Chem. Soc.,

Chem. Commun., 1994, 2659–2660.189 K. Sanda, L. Rigal and A. Gaset, Carbohydr. Res., 1989, 187, 15–23.190 K. Sanda, L. Rigal, M. Delmas and A. Gaset, Synthesis, 1992,

541–542.191 P. Villain-Guillot, M. Gualtieri, L. Bastide, F. Roquet, J. Martinez,

M. Amblard, M. Pugniere and J. P. Leonetti, J. Med. Chem., 2007,50, 4195–4204.

192 F. H. Newth and L. F. Wiggins, J. Chem. Soc., 1947, 396–398.193 M. K. Jogia, V. Vakamoce and R. T. Weavers, Aust. J. Chem., 1985,

38, 1009–1016.194 R. Bognar, P. Herczegh, M. Zsely and G. Batta, Carbohydr. Res.,

1987, 164, 465–469.195 A. C. Cope, 1963.196 P. Gupta, S. K. Singh, A. Pathak and B. Kundu, Tetrahedron, 2002,

58, 10469–10474.197 D. Chundury and H. H. Szmant, Ind. Eng. Chem. Prod. Res. Dev.,

1981, 20, 158–163.198 M. Oikawa, M. Ikoma and M. Sasaki, Tetrahedron Lett., 2005, 46,

415–418.199 T. Elhajj, J. C. Martin and G. Descotes, J. Heterocycl. Chem., 1983,

20, 233–235.

200 J. R. de Freitas Filho, R. M. Srivastava, Y. Soro, L. Cottier and G.Descotes, J. Carbohydr. Chem., 2001, 20, 561–568.

201 D. Schinzer, E. Bourguet and S. Ducki, Chem. Eur. J., 2004, 10,3217–3224.

202 H. Bredereck, Ber. Dtsch. Chem. Ges. B, 1932, 65, 1833–1838.203 T. A. Lewis, L. Bayless, J. B. Eckman, J. L. Ellis, G. Grewal, L.

Libertine, J. Marie Nicolas, R. T. Scannell, B. F. Wels, K. Wenbergand D. M. Wypij, Bioorg. Med. Chem. Lett., 2004, 14, 2265–2268.

204 R. L. Dow, R. C. Kelly, I. Schletter and W. Wierenga, Synth.Commun., 1981, 11, 43–53.

205 I. Iovel, K. Mertins, J. Kischel, A. Zapf and M. Beller, Angew.Chem., Int. Ed., 2005, 44, 3913–3917.

206 M. Cunningham and C. Doree, Biochem. J., 1914, 8, 438–447.207 (a) J. J. Bozell, L. Moens, D. C. Elliott, Y. Wang, G. G. Neuen-

scwander, S. W. Fitzpatrick, R. J. Bilski and J. L. Jarnefeld,Resour., Conserv. Recycl., 2000, 28, 227–239; (b) D. M. Alonso,J. Q. Bond and J. A. Dumesic, Green Chem., 2010, 12, 1493–1513.

208 J. Horvat, B. Klaic, B. Metelko and V. Sunjic, Tetrahedron Lett.,1985, 26, 2111–2114.

209 (a) K. D. Baugh and P. L. Mccarty, Biotechnol. Bioeng., 1988, 31,50–61; (b) B. F. M. Kuster and H. S. Vanderbaan, Carbohydr. Res.,1977, 54, 165–176; (c) K. R. Heimlich and A. N. Martin, J. Am.Pharm. Assoc., 1960, 49, 592–597; (d) H. P. Teunissen, Recl. Trav.Chim. Pays-Bas, 1930, 49, 784–826; (e) S. Mckibbins, J. F. Harrisand J. F. Saeman, J. Chromatogr., A, 1961, 5, 207.

210 B. Girisuta, L. P. B. M. Janssen and H. J. Heeres, Green Chem.,2006, 8, 701–709.

211 G. C. A. Luijkx, F. Vanrantwijk and H. Vanbekkum, Carbohydr.Res., 1993, 242, 131–139.

212 T. Soldo, I. Blank and T. Hofmann, Chem. Senses, 2003, 28, 371–379.

213 H. Ottinger, T. Soldo and T. Hofmann, J. Agric. Food Chem., 2003,51, 1035–1041.

214 T. Soldo and T. Hofmann, J. Agric. Food Chem., 2005, 53, 9165–9171.

215 (a) J. Koch, M. Pischetsrieder, K. Polborn and T. Severin,Carbohydr. Res., 1998, 313, 117–123; (b) O. Pachmayr, F. Ledland T. Severin, Z. Lebensm.-Unters. Forsch., 1986, 182, 294–297.

216 O. Frank, H. Ottinger and T. Hofmann, J. Agric. Food Chem., 2001,49, 231–238.

217 J. M. Timko and D. J. Cram, J. Am. Chem. Soc., 1974, 96, 7159–7160.

218 S. T. Waddell, J. M. Eckert and T. A. Blizzard, Heterocycles, 1996,43, 2325–2332.


Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

28

Febr

uary

201

1 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

0GC

0040

1DView Online


viewonline green chemistry dynamicarticlelinks …szolcsanyi/education/files/chemia...

Documents