EMF) and 5-Hydroxymethylfurfural

Direct conversion of carbohydrates into 5-ethoxymethylfurfural (EMF) and 5-hydroxymethylfurfural

(HMF) catalysed by MoO2Cl2(H2O)2

Pereira, Juliana Centro de Química Estrutural, Instituto Superior Técnico, Av. Rovisco Pais, Lisboa Portugal

Abstract This work reports a one-pot synthesis of 5-ethoxymethylfurfural (EMF) from fructose catalysed by different dioxo- molybdenum complexes using different solvents and temperatures. This method has the advantage of using an efficient, economical, environmental catalyst with an easy preparation. The best result obtained for EMF (53%) was observed using a mixture of ethanol/THF (5:2) catalysed by MoO2Cl2(H2O)2 (10 mol%) at 120ºC, after 17 h. The possible use of

MoO2Cl2(H2O)2 in more than one catalytic cycle was also studied and it was verified that the yield of EMF was reduced 2.5 times on the fourth cycle. The conversion of fructose into EMF in a large scale (10 mmol) was also investigated and enabled a good yield of EMF. The synthesis of EMF from other carbohydrates such as inulin and sucrose, was also explored giving EMF with 40% and 23% yield, respectively. The dehydration of fructose into HMF was achieved in good yield (75%) from fructose using MoO2Cl2(H2O)2 in DMSO at 120ºC after 30 minutes.

Keywords: Biomass, carbohydrates, 5-ethoxymethylfurfural (EMF), 5-hidroximethylfurfural (HMF), dioxo-molybdenum complexes.

1. Introduction Due to environmental problems and the decreasing of fossil reserves, the necessity to develop successful methods to produce chemical and fuels from renewable feedstocks emerged. An alternative for non-renewable resources is the use of biomass, renewable carbon sources, where the major constituents are carbohydrates.[1, 2] These compounds are a promising alternative since they are relatively economic, environmentally friendly and can be found in great amount on Earth.[3] The conversion of biomass to organic chemicals and liquid fuels using an efficient catalyst is one of the most important processes in biorefinary.[1, 3, 4] To produce chemicals and fuels, like HMF, EMF or other derivatives from biomass, a catalyst capable of promoting the dehydration of monosaccharides is essential, such as homogeneous mineral acid, Brønsted acidic ionic liquids (IL), Lewis acidic metal halides and recyclable heterogeneous catalysts.[5] The successive transformation of HMF into other value added chemicals, such as promising next generation polyester building block monomers (2,5-furandicarboxylic acid (FDCA), 2,5-bis(hydroxymethyl)furan (BHMF), and 2,5- bis(hydroxymethyl)tetrahydrofuran (BHMTF)) and potential biofuel candidates (2,5-dimethylfuran (2,5-DMF), 5- ethoxymethylfurfural (EMF), ethyl levulinate (EL) and γ-valerolactone (γVL)) (Figure 1) has also been explored using HMF as a starting substrate or directly from biomass in a one-pot process.[6]

O O HO OH HO OH

OH OH BHMF BHMTF O HO OH O O O O O n O HO HO OH OH OH Cellulose Hydrolysis FDCA

Pretreatment O HO Hydrolysis OH OH O O 2,5-DMF O O Isomerization OH Dehydration O H OEt HO OH HO H OH OH OH OH O Glucose Frutose EMF HMF

2-MF

Hydrolysis

OH HO O O O HO O HO OH OH O HO EtO OH OH Sucrose O O EL LA O O

γVL!

Figure 1. Production of liquid fuels and other chemicals from biomass.[5]

The application of HMF is indeed versatile and high HMF yields were already achieved. However, HMF presents a high cost and this fact is a limitation to sustainable use as a potential replacement for petroleum resources.[2, 5] The most abundant and cheapest monosaccharide is the glucose, a hexose. This carbohydrate is being investigated on the transformation into chemicals and biofuels.[2, 7] The use of glucose to afford HMF or other 2,5-disubstituted furan derivatives has an increased difficulty because it requires a bifunctional catalyst, allowing the isomerization of glucose to fructose and later dehydration of fructose (Figure 2). In general, fructose is much more reactive and selective toward HMF than glucose.[6]

OH HO OH O HO OH HO O O O + O + + O HO H H O H OH OH OH HO H HO -H O OH OH 2 -H2O -H2O OH OH OH Glucose Fructose HMF Figure 2. Isomerization of glucose and dehydration of fructose into HMF.[6]

Solvents also play an important role in the improvement of HMF and EMF yields. Easy separation and purity make the process environmentally and economically competitive.[5] High yields of HMF were achieved in the presence of dimethylsulfoxide (DMSO) and dimethylformamide (DMF), methyl isobutyl ketone (MIBK) and ionic liquids (ILs). However, a potential drawback of the ILs solvent mediated process is that ILs are expensive and the separation of HMF from high boiling ILs is energy intensive. Besides the cost factor, ILs is also deactivated by water, which is formed during the dehydration reaction. The high boiling points of DMSO and DMF also pose similar challenges for HMF separation, and therefore these processes are economically unfavorable on a commercial scale. Additionally, high concentrations of oligomeric species, humins, are also form as by-products in organic solvent mediated dehydration reactions. The polar organic solvents have a disadvantage since there is a strong affinity with the hydroxyl group of HMF, resulting in a difficulty to separate both by extraction. One way to solve this problem is the etherification of hydroxyl group in HMF with ethanol, methanol, etc.[2, 8] Ethanol is a green solvent inexpensive and can also be produced from biomass.[9-11] Another advantage of using alcohols as solvents is the supply of humin formation.[9] Recently the etherification of HMF has attracted attention, since the ethers of HMF are a great addition to diesel. In the case of 5-ethoxymethylfurfural (EMF) its own physical and chemical properties make it a remarkable biofuel. EMF has a high energy density of 8.7 kWh/L, similar to that of regular gasoline (8.8 kWh/L), nearly as good as that of diesel (9.7 kWh/L), and significantly higher than that of ethanol (6.1 kWh/L).[2, 8, 9, 11] Currently, there are several methods on the synthesis of EMF. It is undoubted that the etherification of hydroxyl group in HMF with ethanol is the most effective way. However, the practical large-scale synthesis of EMF from HMF is limited due to the high cost of HMF. Using fructose as a start material, since it is inexpensive and renewable, and a different alcohol as a solvent to do the dehydration into HMF following by the etherification to the correspondent ether in one-pot synthesis, saves time, energy and solvent (Figure 3).[12]

HO OH O O O -3H O Cat, EtOH OH 2 O O H OH -H2O H OEt

OH OH

Fructose HMF EMF Figure 3. Conversion of fructose into EMF.[12]

Molybdenum-based catalyst has been applied in many organic reactions. In last decade, high valent oxo- molybdenum complexes such as MoO2Cl2 have been proved to be excellent catalysts for the reduction of organic compounds such as aldehydes[13], ketones[13], esters[14], amides[15], imines[16], sulfoxides[17] and N-oxides[17]. The development of environmental friendly process for the synthesis of HMF, EMF and other derivatives from renewables still represents a great challenge.[18] In the present work, the conversion of carbohydrates into HMF or EMF

2 catalysed by several dioxo-molybdenum complexes in water, in polar aprotic solvents or in different alcohols was investigated. 2. Results and discussion Initially, the reaction of fructose was studied with several dioxo-molybdenum catalysts, solvent and temperatures in order to find the best reaction conditions.

2.1. Synthesis of EMF 2.1.1. Effect of catalyst amount

The effect of the amount of the catalyst MoO2Cl2(H2O)2 [19] in the conversion of fructose into EMF at 120ºC after 17 h is showed in figure 4. An increase of catalyst amount led to an increase of EMF yield, but also an increase of the by- product EL. The increase of EMF with the increase of the catalyst amount is probably due to the higher number and availability of catalytic active sites.[2] EMF yield reaches a maximum of 50% when the amount of catalyst increases to 30 mol%. As evidenced in figure 4, increasing the amount of MoO2Cl2(H2O)2 allows the increase of EMF and EL yields.

45 EMF 40

Yield (%) Yield 25

20 EL

10 10 15 20 25 30 MoO2Cl2(H2O)2 (mol%)

Figure 4. The effect of catalyst amount on the conversion of fructose into EMF. Reaction conditions: fructose, 1 mmol; ethanol, 5 mL; 120ºC; 17h.

2.1.2. Effect of catalytic activity of different dioxo-molybdenum complexes

Dehydration of fructose was carried out with the dioxo-molybdenum complexes MoO2Cl2(H2O)2, MoO2(acac)2,

MoO2Cl2(DMF)2, MoO2Cl2(DMSO)2 and MoO2Cl2(OPPh3)2.The reactions were performed using 30 mol% of these catalysts in ethanol at 120ºC and 150ºC during 17 hours (Figure 5). (a) (b)

60 HMF (%) HMF (%) 60 EMF (%) EMF (%) EL (%) EL (%) 50 50

40 40

30 30 Yield (%) Yield Yield (%) Yield 20 20

10 10

0 0 1 2 3 4 5 1 2 3 4 5 Figure 5. The effect of different molybdenum oxo-complexes on the conversion of fructose into EMF. Reaction conditions: fructose, 0.5 mmol, except for

MoO2Cl2(H2O)2, 1 mmol; 1: MoO2Cl2(H2O)2; 2: MoO2Cl2(DMF)2; 3: MoO2Cl2(DMSO)2; 4: MoO2Cl2(OPPh3)2; 5: MoO2(acac)2; 30 mol%; ethanol, 5 mL; 17h at (a) 120ºC and (b) 150ºC.

The best result was achieved using MoO2Cl2(H2O)2 at 120ºC, producing 50% yield of EMF and 22% yield of EL. At

150ºC with MoO2Cl2(H2O)2 as catalyst was observed a decrease on EMF yield (30%) and an increase of EL yield (36%), suggesting the conversion of EMF into EL with the increase of temperature.

In the presence of MoO2Cl2(DMF)2 was observed the formation of EMF with 32% and 29% yields at 120ºC and 150ºC, respectively. Using this catalyst, the yield of EL was 20% (at 120ºC) and 33% (at 150ºC), which indicates that

MoO2Cl2(DMF)2 also promotes the decomposition of EMF into EL with the increase of temperature. An improvement of EL yield and a decrease of EMF yield with the temperature was also verified for the reaction of fructose catalysed by

MoO2Cl2(DMSO)2. In the reaction carried out at 120ºC with MoO2Cl2(DMSO)2, the HMF intermediate was also detected with 15% yield.

The complex MoO2Cl2(OPPh3)2 also catalysed the conversion of fructose into EMF and EL, but the increase in the temperature did not affect considerably the distribution of the products. At 120ºC using the complexes MoO2Cl2(DMSO)2 or MoO2Cl2(OPPh3)2, the EL was detected as the major product of the fructose conversion. Finally, the dioxo-complex

MoO2(acac)2 was not efficient in the reaction of fructose at 120ºC and 150ºC.

2.1.3. Effect of different co-solvents To improve the EMF yield, THF, DMSO, DMF and dioxane were added as a co-solvent to a solution of ethanol. The reactions were performed with 10 mol% of MoO2Cl2(H2O)2 at 120ºC during 17 hours. As it can be observed in figure 6, adding THF as a co-solvent in ethanol improved the EMF yield of 26% to 53% and it was also detected a residual amount of HMF (5%). Dioxane had also a positive effect on the dehydration-etherification reactions producing 16% yield of HMF and improved the yield of EMF to 33%. The yield of EMF was lower, but the higher yield of HMF (41%) was achieved in a solution of ethanol/DMSO (5:2). HMF was the only product detected in a mixture of ethanol/DMF, suggesting that the etherification of HMF with ethanol was inhibited or proceeded more slowly under this reaction conditions. The best result of EMF was achieved with addition of THF (2mL) in ethanol (5 mL), allowing 53% yield of EMF instead of 26% yield, using only ethanol.

40 HMF (%) EMF (%) EL (%) 30 Yield (%) Yield 20

0 1 2 3 4 5

Figure 6. The effect of different co-solvents on the conversion of fructose into EMF. Reaction conditions: fructose, 1 mmol; MoO2Cl2(H2O)2, 10 mol% 1: EtOH, 2: EtOH/THF, 3: EtOH/Dioxane, 4: EtOH/DMSO, 5: EtOH/DMF, (5:2); 120ºC; 17h.

2.1.4. Effect of THF as a co-solvent Addition of THF as a co-solvent into 5 mL of ethanol increases significantly the EMF yield obtained from fructose using 10 mol% of MoO2Cl2(H2O)2 (Figure 7). In pure ethanol, EMF was obtained in 26% yield and after the addition of THF (2 mL), the yield increased to a maximum of 53%. For 3.5 mL of THF, HMF was afforded with 24% yield, however the yield of EMF did not increase. Higher volumes of THF increase HMF yields and decrease EMF and EL products, which suggesting that for higher amounts of THF or lower volumes of ethanol, the etherification of HMF with ethanol was inhibited or proceeded more slowly.

40 EMF (%)

Yield (%) Yield HMF (%) 20

10 EL (%)

0 0 1 2 3 4 5 THF (mL)

Figure 7. The effect of the addition of THF as co-solvent on the conversion of fructose in ethanol. Reaction conditions: fructose, 1 mmol; MoO2Cl2(H2O)2, 10 mol%; Ethanol, 5 mL, 120ºC; 17h.

2.1.5. Effect of catalyst amount in conversion of fructose into EMF using a mixture of ethanol/THF

Figure 8 shows the effect of the amount of catalyst MoO2Cl2(H2O)2 on the synthesis of EMF from fructose in a mixture of ethanol/THF (5:2) at 120ºC. In the absence of catalyst, the reaction of fructose gave only 6% yield of HMF after

17 hours. The yield of EMF was improved by increasing the amount of MoO2Cl2(H2O)2 from 2.5 mol% to 30 mol%. EMF yields of 43%, 50%, 53%, 55% and 60% were obtained with 2.5 mol%, 5 mol%, 10 mol%, 20 mol% and 30 mol% of

4 catalyst amount, respectively. Higher amounts of MoO2Cl2(H2O)2 improves the EMF and EL yields. The increase of EMF yields with the increase of MoO2Cl2(H2O)2 could be attributed to an increase of the number of catalytically active sites.[2] As seen in figure 8, the EMF yield reaches a maximum of 60% in the presence of 30 mol% of catalyst. When the amount of catalyst changed from 10 mol% to 30 mol%, a small increase on the EMF yield (53% to 60%) was observed, therefore the next studies were performed with 10 mol% of MoO2Cl2(H2O)2.

70 EMF (%) 60

30 Yield (%) Yield EL (%) 20

10 HMF (%) 0 0 5 10 15 20 25 30 MoO2Cl2(H2O)2 (mol %)

Figure 8. The effect of the amount of catalyst MoO2Cl2(H2O)2 on the conversion of fructose into EMF. Reaction conditions: fructose, 1 mmol; ethanol, 5 mL; THF, 2 mL; 120ºC; 17h.

2.1.6. Effect of reaction temperature in conversion of fructose into EMF The effect of reaction temperature on the conversion of fructose into EMF was also investigated using the catalyst

MoO2Cl2(H2O)2 in a mixture of ethanol/THF (5:2) during 17 hours. The results obtained are shown in figure 9.

60 EMF (%)

Yield (%) Yield EL (%) 20

10 HMF (%) 0 40 60 80 100 120 140 160 Temperature (ºC)

Figure 9. The effect of reaction temperature on the conversion of fructose into EMF. Reaction conditions: fructose, 1 mmol; MoO2Cl2(H2O)2, 10 mol%; Ethanol, 5 mL; THF, 2 mL; 17h.

The dehydration of fructose was carried out at different temperatures from 25ºC to 150°C. At room temperature, 25ºC, the reaction did not occur and at 80ºC a mixture of HMF (34%) and EMF (15%) was afforded. The highest amount of HMF was obtained at this temperature. An increase in the reaction temperature improves the EMF yield and the HMF yield decreases, up to 120ºC, as a result of HMF etherification into EMF. The maximum yield of EMF (53%) was obtained at 120ºC. Higher temperatures accelerate the rate of etherification of HMF into EMF and increase the yield of the by- product EL.[8] At 135ºC and 150ºC, the HMF product is inexistent. Figure 9 shows a significant effect of reaction temperature on the products distribution.

2.1.7. Reaction of fructose using different alcohols To understand the alcohol effect on the etherification, the reaction of fructose was promoted in the presence of ethanol, methanol, propan-2-ol and in a mixture of alcohol/THF. It was ensured that fructose solubilizes in all the solvents used, since the solubility may be a limiting factor in the dehydration reaction.[20] As it is observed in table 1, the product formed depends on which alcohol is used. Ethanol, as it is shown previously, leads to the etherification of HMF into EMF. On the other hand, in the presence of methanol and propan-2-ol, instead the formation of EMF, the products obtained were 5-methoxymethylfurfural (MMF) and 5-i-propoxymethylfurfural (IMF), respectively. Besides the behaviour of the alcohol as a solvent, it also acts as a reagent in the reaction. The reaction of fructose in ethanol produced EMF with 28% yield and the reaction in methanol afforded MMF and methyl levulinate (ML) in 28% yield, for each one, the last reaction was proceeded in presence of 30 mol% of MoO2Cl2(H2O)2 (Table 1, entries 1 and 5). The best yield (44%) was obtained for the formation of IMF in propan-2-ol (Table 1, entry 3). On the other hand, when the reactions were performed in a

5 mixture of alcohol/THF, the yields of alkoxymethyl ethers of HMF were improved except with the propan-2-ol/THF mixture (Table 1, entries 3 and 4). The best result achieved for HMF was 42% in presence of propan-2-ol/THF (Table 1, entry 4). The higher yield of alkoxymethyl ether of HMF was obtained in a mixture of ethanol/THF in 53% yield (EMF) (Table 1, entry 2).

Table 1. Conversion of fructose into EMF, MMF and IMF using different alcohols or a mixture of alcohol/THF.a Entry Solvent Volume (mL) HMF (%) RMF (%) RL (%) 1 Ethanol 5 0 28 11 2 Ethanol/THF 5:2 5 53 9 3 Propan-2-ol 10 0 44 3 4 Propan-2-ol/THF 5:2 42 35 0 5 b Methanol 10 0 28 28 6 Methanol/THF 5:2 0 39 15 a b All reactions were carried out with 1 mmol of fructose in presence of MoO2Cl2(H2O)2 (10 mol%). Reaction was carried out with 30 mol% of MoO2Cl2(H2O)2.

2.1.8. Time course of the conversion of fructose into EMF Figure 10 shows the time course of the reaction of fructose in a mixture ethanol/THF at 120ºC catalysed by

MoO2Cl2(H2O)2. After one hour, the maximum yield of HMF (48%) was reached, along with a small amount of EMF and EL was not detected. As time progresses, up to 8 hours, the yield of HMF decreased and EMF yield as well as EL yield increased. The best EMF yield (56%) was observed after ten hours of reaction. Figure 10 also shows that HMF is a intermediate, formed by the dehydration of fructose, being subsequently etherified into EMF.[8]

50 EMF(%) 40

30 Yield (%) Yield

20 HMF (%) EL (%) 10

0 0 2 4 6 8 10 12 14 16 Time (h)

Figure 10.Time course of the conversion of fructose into EMF. Reaction conditions: fructose, 1 mmol; MoO2Cl2(H2O)2, 10 mol%; Ethanol, 5 mL; THF, 2 mL; 120ºC.

2.1.9. Synthesis of EMF from glucose In order to obtain EMF from another cheaper and renewable source, the synthesis of EMF from glucose was also investigated. The reaction was carried out in ethanol (2-13 mL) and in a mixture of ethanol/THF (5:2) with different temperatures (100ºC-180ºC) and several amounts of MoO2Cl2(H2O)2 (10-30 mol%), however HMF, EMF and EL were not detected in the reaction mixture. The absence of these compounds may be justified by the inability of MoO2Cl2(H2O)2 to isomerize glucose into fructose, since it is a crucial step for the formation of the referred compounds. Previous reports showed that, in acidic conditions, glucose reacts with alcohols, generating the ethyl glucopyranoside (Figure 11).[2]

OH OH O EtOH, H+ O HO HO OH OEt HO HO OH OH D-Glucose Ethyl D-glucopyranoside Figure 11. Reaction of D-glucose with ethanol in acid conditions.

2.1.10 Synthesis of EMF from sucrose and inulin In order to explore the substrate scope of our catalyst system, the synthesis of EMF from other carbohydrates was investigated. Sucrose (the most abundant and cheapest disaccharide) and inulin (a polysaccharide) were employed as

6 starting material for the production of EMF, and the results obtained are shown in figure 12.[12] Sucrose molecule contains one fructose unit and one glucose unit, while inulin has various units of fructose and just contains one molecule of terminal glucose.[8] The reactions were carried out in a mixture of ethanol/THF (5:2) at 120ºC with 10 mol% of

MoO2Cl2(H2O)2 during 17 hours, producing EMF in 40% and 23% yields from inulin and sucrose, respectively. The results obtained show that MoO2Cl2(H2O)2 not only catalysed the dehydration and the etherification reactions but it also promotes the hydrolysis of glycosidic bonds. The EMF yield obtained from sucrose was much lower than the EMF yield observed from inulin and fructose, probably due to the inability of the catalyst to convert glucose into EMF.

HMF (%) 50 EMF (%) EL (%) 40

30 Yield (%) Yield 20

0 Fructose Inulin Sucrose

Figure 12. Synthesis of EMF from various carbohydrates. Reaction conditions: 1 mmol of hexose; MoO2Cl2(H2O)2, 10 mol%; Ethanol, 5 mL; THF, 2 mL; 120ºC; 17h.

2.1.11 Use of catalyst MoO2Cl2(H2O)2 in several cycles

In order to study the possible use of the complex MoO2Cl2(H2O)2 (10 mol%) in more than one catalytic cycle, it was carried out successive reaction of fructose by sequential addition of this carbohydrate to the reaction mixture at 120ºC for 17 hours, during four cycles. The reactions were monitored by 1H NMR and the obtained results showed that the EMF yield decrease from 53% in the first run to 22% after the fourth run. As it can be seen in figure 13, the yield of EMF decreases gradually over the catalytic cycles.

40 HMF (%) EMF (%) EL (%) 30 Yield (%) Yield 20

0 1 2 3 4 Number of cycles

Figure 13. Use of MoO2Cl2(H2O)2 catalyst in several catalytic cycles. Reaction conditions: fructose, 1 mmol (for each cycle); MoO2Cl2(H2O)2, 10 mol%; Ethanol, 5 mL; THF, 2 mL; 120ºC; 17h.

2.1.12 Synthesis of EMF in large-scale In this work was also investigated the direct conversion of fructose into EMF in large scale (10 mmol) catalysed by

MoO2Cl2(H2O)2 (10 mol%). The reaction was carried out at 120ºC for 17 hours, allowing the formation of EMF in 53%, with a similar yield obtained with 1 mmol of fructose. This result demonstrated the efficiency of the catalyst for the synthesis of EMF in large scale.

2.2 Synthesis of HMF 2.2.1 Effect of different solvents In this work was also studied the selective conversion of carbohydrates into HMF. With this goal, initially was studied the dehydration reaction of fructose catalysed by MoO2Cl2(H2O)2 (10 mol%) at 150ºC and 170ºC in water, allowing the formation of HMF with only 3% and 22% yields, respectively, after 17 hours. The reaction was also investigated with several aprotic polar solvents including DMSO, DMF, THF and dioxane at 120ºC during 2 hours and the best result of HMF (52%) was achieved with DMSO (Table 2, entry 1). THF, DMF and dioxane also promoted the dehydration of fructose, affording low yields of HMF (30-33%).

Table 2. Dehydration of fructose using different solvents. Entrada DMSO (mL) THF (mL) DMF (mL) Dioxano (mL) HMF (%) 1 5 0 0 0 52 2 0 10 0 0 30 3 0 0 7 0 30 4 0 0 0 7 33

Reaction conditions: fructose, 1 mmol; MoO2Cl2(H2O)2, 10 mol%; 120ºC; 2h.

2.2.2 Time course of the HMF formation The formation of HMF was also monitored over time using fructose, sucrose and inulin as substrates in the presence of 10 mol% of MoO2Cl2(H2O)2 in DMSO at 120ºC. The best yield of HMF (75%) was achieved after 30 minutes of reaction from fructose (Table 3, entry 2). The obtained results demonstrated that the yield of HMF increased until 30 minutes and then decreased to 52% after 2 hours, probably due to the decomposition of HMF into by-products (Table 3, entries 1-5). The formation of HMF from inulin and sucrose was also investigated and it was observed that for the same reaction time, the yield of HMF was lower than when was used fructose as starting material (Table 3, entries 6-11). These results can be justified by the hydrolysis of sucrose and inulin into their hexoses, before the dehydration into HMF. The dehydration of glucose in DMSO was also studied but did not lead to the formation of HMF. Despite the good yield of HMF (75%) obtained in DMSO, this solvent has the disadvantage to have a high boiling point, needing a large amount of energy or solvent for HMF purification.

Table 3. Synthesis of HMF from fructose, sucrose and inulin in DMSO. Entry Substrate Time (min) HMF (%)b 1 Fructose 15 68 2 Fructose 30 75 3 Fructose 60 72 4 Fructose 90 52 5 Fructose 120 52 6 Inulin 30 35 7 Inulin 60 39 8 Inulin 90 39 9 Sucrose 30 38 10 Sucrose 60 41 11 Sucrose 90 41

Reaction conditions: Hexose, 1 mmol; MoO2Cl2(H2O)2, 10 mol%; DMSO, 5 mL; 120ºC.

3 Conclusions In this work, the conversion of fructose into EMF was investigated using different dioxo-molybdenum complexes as catalysts, various solvents and different temperatures. The best result of EMF yield (53%) was obtained using a mixture of ethanol/THF (5:2) catalysed by MoO2Cl2(H2O)2 (10 mol%) at 120ºC, after 17 h.

The use of MoO2Cl2(H2O)2 in several catalytic cycles was also studied and it was verified that the yield of EMF decreases over four cycles. The use of this catalyst was investigated in a large scale (10 mmol) and a good yield of EMF was obtained. The reaction of fructose was also studied in the presence of different alcohols including methanol and propan-2-ol, and instead the formation of EMF, the products obtained were 5-methoxymethylfurfural (MMF) and 5-i- propoxymethylfurfural (IMF), respectively, in moderate yields. The synthesis of EMF from glucose was also investigated with different reactions conditions, however HMF, EMF and EL were not detected in the reaction mixture. The absence of these compounds may be justified by the inability of

MoO2Cl2(H2O)2 to isomerize glucose into fructose. The EMF product can also be produced from inulin and sucrose with 40% and 23% yield, respectively. The efficiency of the catalyst in the selective conversion of carbohydrates into HMF was tested using DMSO as a solvent and good yields of HMF from fructose were achieved. In this work was reported the first methodology for the one step conversion of carbohydrate, an abundant and cheaper renewable source, into HMF and EMF with moderate to good yield catalysed by dioxo-molybdenum complexes. This method has also the advantage of using an efficient, economical, environmental catalyst with an easy preparation.

4 Experimental 4.1 General procedure for the conversion of carbohydrates into EMF To a Schlenk flask equipped with a J. Young tap was added a solution of carbohydrate (1.0 mmol of hexose) in a mixture ethanol/THF (5 mL:2 mL) and a solution of MoO2Cl2(H2O)2 (10 mol%). The reaction mixture was stirred in a closed Schlenk at 120ºCduring 17 hours.The yields of the products were determined by spectroscopy1H NMR using mesitylene as internal standard.

4.2 General procedure for the conversion of fructose into MMF and IMF To a Schlenk flask equipped with a J. Young tap was added a solution of fructose (1.0 mmol) in alcohol (10 mL) or in a mixture alcohol/THF (5 mL:2 mL) and a solution of MoO2Cl2(H2O)2 (10-30 mol%). The reaction mixture was stirred in a closed Schlenk at 120ºC during 17 hours. The yields of the products were determined by spectroscopy1H NMR using mesitylene as internal standard.

4.3 Use of catalyst MoO2Cl2(H2O)2 in several cycles To a Schlenk flask equipped with a J. Young tap was added a solution of fructose (1.0 mmol) in a mixture ethanol/THF (5:2) and a solution of MoO2Cl2(H2O)2(10 mol%). The reaction mixture was stirred in a closed Schlenk at 120ºC during 17 hours. The reaction mixture was cooled and the yield was determined by 1H NMR spectroscopy using mesytilene (1 mmol) as the internal standard. In the next catalytic cycles, fructose (1.0 mmol), and mesytilene (1.0 mmol) were added to the reaction mixture and stirred for 17 h at 120ºC. The reaction mixture was cooled and the yields were determined by 1H NMR spectroscopy.

4.4 Synthesis of EMF in large-scale To a Schlenk flask equipped with a J. Young tap was added a solution of fructose (10 or 42 mmol) in a mixture ethanol/THF (20 mL:8 mL or 100 mL:40 mL) and a solution of MoO2Cl2(H2O)2 (10 mol%). The reaction mixture was stirred in a closed Schlenk at 120ºC during 17 hours. The yields of the products were determined by spectroscopy1H NMR using mesitylene as internal standard.

4.5 General procedure for the conversion of carbohydrates into HMF To a Schlenk flask equipped with a J. Young tap was added a solution of carbohydrate (1.0 mmol of hexose) in

DMSO (5 mL) and a solution of MoO2Cl2(H2O)2 (10 mol%). The reaction mixture was stirred in a closed Schlenk at 120ºC for various time periods. The yields of the products were determined by spectroscopy 1H NMR using mesitylene as internal standard.

4.6 Characterization of the products 1 5-Hydroxymethylfurfural (HMF). H RMN (300 MHz, CDCl3) δ 3.22 (s, 1H), 4.67 (s, 2H), 6.49 (d, J= 3.0 Hz, 1H), 7.20 (d, 13 J= 3.0 Hz, 1H), 9.52 (s, 1H) ppm. C RMN (300 MHz, CDCl3) δ 57.49, 110.10, 123.43, 152.27, 161.08, 177.88 ppm. 1 5- Ethoxymethylfurfural (EMF). H RMN (300 MHz, CDCl3) δ 1.20 (t, J= 9.0 Hz, J= 6.0 Hz, 3H), 3.55 (q, J= 6.0 Hz, J= 13 9.0 Hz, 2H), 4.49 (s, 2H), 6.49 (d, J= 3.0 Hz, 1H), 7.18 (d, J= 3.0 Hz, 1H), 9.57 (s,1H) ppm. C RMN (300 MHz, CDCl3) δ 15.10, 64.79, 66.65, 111.05, 122.01, 152.62, 158.82, 177.74 ppm.

1 5-i-Propoxymethylfurfural (IMF). H RMN (400 MHz, CDCl3) δ 1.17 (d, J= 8.0 Hz, 6H), 3.64-3.73 (m,1H), 4.50 (s, 2H), 13 6.48 (d, J= 4.0 Hz, 1H), 7.18 (d, J= 4.0 Hz, 1H), 9.57 (s, 1H) ppm. C RMN (400 MHz, CDCl3) δ 22.00, 62.54, 72.17, 110.77, 122.20, 152.5, 159.4, 177.6 ppm. 1 5-Methoxymethylfurfural (MMF). H RMN (300 MHz, CDCl3) δ 3.39 (s, 3H), 4.46 (s, 2H), 6.51 (d, J= 3.0 Hz, 1H), 7.19 (d, 13 J= 6.0 Hz, 1H), 9.59 (s, 1H) ppm. C RMN (300 MHz, CDCl3) δ 58.79, 66.63, 111.29, 122.05, 152.69, 158.35, 177.84 ppm. 1 Ethyl Levulinate (EL). H RMN (400 MHz, CDCl3) δ 1.22 (t, J= 8.0 Hz, 3H), 2.16 (s, 3H), 2.54 (t, J= 8.0 Hz, J= 4.0 Hz, 13 2H), 2.72 (t, J= 8.0 Hz, 2H) 4.10 (q, J= 8.0 Hz, J= 4.0 Hz, 2H) ppm. C RMN (400 MHz, CDCl3) δ 14.24, 28.10, 29.95, 38.03, 60.69, 172.81, 206.76 ppm. 1 1 Isopropyl levulinate (IL). H RMN (400 MHz, CDCl3) δ H RMN (400 MHz, CDCl3) δ 1.21 (d, J = 4.0 Hz, 3H), 1.23 (d, J = 4.0 Hz, 3H), 2.17 (s, 3H), 2.72 (t, J = 4.0 Hz, J = 8.0 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H), 4.94-5.01 (m, 1H) ppm. 13C RMN

(400 MHz, CDCl3) δ 21.91, 28.53, 30.00, 38.14, 68.11, 172.35, 206.82 ppm. 1 Methyl levulinate (ML). H RMN (400 MHz, CDCl3) δ 2.18 (s, 3H), 2.56 (t, J= 4.0 Hz, J= 8.0 Hz, 2H), 2.74 (t, J= 8.0 Hz, 13 2H), 3.66 (s, 3H) ppm. C RMN (400 MHz, CDCl3) δ 27.86, 29.97, 38.07, 51.91, 173.33, 206.74 ppm.

Acknowledgements The authors thank the project UID/QUI/00100/2013 and the Portuguese NMR Network (IST –UTL Center) for providing access to the NMR facilities.

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