Conversion of d-Fructose to 5-(Hydroxymethyl)furfural: Evaluating

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Conversion of D-Fructose to 5-(Hydroxymethyl)furfural: Evaluating Batch and Continuous Flow Conditions by Design of Experiments and In-line FTIR Monitoring. Renan Galaverna, Márcia Cristina Breitkreitz, and Julio Cezar Pastre ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b04643 • Publication Date (Web): 30 Jan 2018 Downloaded from http://pubs.acs.org on February 2, 2018

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ACS Sustainable Chemistry & Engineering

Conversion of D-Fructose to 5(Hydroxymethyl)furfural: Evaluating Batch and Continuous Flow Conditions by Design of Experiments and In-line FTIR Monitoring Renan Galaverna,† Márcia C. Breitkreitz,† Julio C. Pastre.*† †

Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154 - Zip Code 13083-

970, Campinas, SP, Brazil. * †

Correspondence to Julio Cezar Pastre, Institute of Chemistry, University of Campinas -

UNICAMP, PO Box 6154 - Zip Code 13083-970, Campinas, SP, Brazil. E-mail: [email protected]. Phone: +55 (19) 3521 31 43. KEYWORDS. HMF, D-Fructose, batch, continuous flow regime, design of experiments, FTIR

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ABSTRACT. The dehydration reaction of D-(-)-Fructose into 5-(hydroxymethyl)furfural (HMF) in both batch and continuous flow conditions was comprehensively studied using the statistical tool Design of Experiments (DoE), employing i-PrOH/DMSO as solvent system in the presence of the solid acid catalyst Amberlyst-15. Initially, screening of different alcohols (MeOH, EtOH, i-PrOH and t-BuOH) showed that i-PrOH provides better selectivity and yield compared to the other alcohols, along with minimum formation of by-products when associated with small amounts of DMSO (15% v/v) as a co-solvent. To confirm the selectivity of the reaction, all the possible by-products (HMF-ethers and/or ketals) formed during the reaction between HMF and iPrOH were synthesized. Factors like temperature, amount of DMSO, time (flow rate), and catalyst loading were evaluated by a full factorial design and the results indicated that temperature presents the greatest influence in both batch (HMF in 71% yield) and continuous flow regime (HMF in 95% yield). In addition, a FTIR device was coupled to the continuous flow micro reactor, allowing for the first time constant in-line monitoring for this transformation, thereby showing the long-term stability of Amberlyst-15 and process robustness.


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INTRODUCTION. The search for new bio-based chemicals has motivated both academic and industrial sectors over the last decade. This increasing interest is due to the large number of valuable compounds that can be obtained from biomass.1 In particular, the production of furfural and its derivatives, such as 5-(hydroxymethyl)furfural (HMF), has been extensively explored by several groups in view of its flexibility to achieve feedstocks for bulk chemicals, polymers, solvents, and fuels (Scheme 1).2,3 Furthermore, furan-based compounds are listed among the ten most important classes of molecules that can be obtained from biomass by the US Department of Energy.1

Scheme 1. Bio-based chemicals obtained from HMF.

HMF is mostly synthesized from C6 carbohydrates. Among them, D-Fructose is the sugar of choice in view of its similar structure, providing higher yield by its rapid and direct dehydration. In contrast, there are several studies employing other C6 carbohydrates which involve additional


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steps such as hydrolysis, isomerization, and subsequently dehydration, leading in most cases to low yields and low selectivity for HMF.4-14 The synthesis of HMF under acidic conditions was firstly evaluated in 1875 by Grote and Tollens.15 After this seminal work, different reaction conditions and substrates have been proposed and successfully described by several groups.5-14 However, few studies have delivered a cost-efficient production of this important bio-based compound. Consequently, so far, there is no industrial unit for HMF production due to its high production cost. As reported by Vogel and co-workers,16 the production of HMF from biomass could be economically and industrially viable at a price lower than 2 euros/kg. In this context, a batch process would not be the best choice, since in most cases, high temperature, reaction time, exhaustive purification and workup processes are required to afford highly pure HMF.17 In contrast, continuous flow processing offers significant improvement for this procedure, mainly due to the possibility of producing highly pure HMF by a simple single-pass continuous flow operation. In addition, due to the easy coupling of flow to analytical tools for the in-line monitoring, novel opportunities in the field of process analytical technology (PAT) could be done for HMF synthesis.18 Indeed, very recently, continuous flow processing has been successfully applied to the synthesis of HMF from C6-sugars. Hermans and Aellig have shown the conversion of DFructose into HMF in batch and continuous flow regime using heterogeneous catalysis.19 Xiao and co-workers showed the fructose and glucose dehydration reaction into HMF using a combination of super-hydrophobic mesoporous polymer acid and base catalyst (P-SO3H-154) in batch and continuous flow conditions.20 Continuous flow processing was also applied to the evaluation of ordered and non-ordered propylsulfonic acid-functionalized porous silica by Dumesic and co-workers.21 Kim and co-workers developed an integrated continuous flow


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process to prepare a series of furan based chemicals including HMF using a sulfonic acidfunctionalized silica capillary as a micro reactor.22 Afonso and co-workers also explored continuous flow conditions for fructose and glucose dehydration using an ionic liquid as reaction medium and Amberlyst-15 or sulfuric acid as acid catalysts.

23,24

In these studies, HMF was

produced in up to 91% yield with high purity. Since 1980, DMSO has been used as solvent or co-solvent for HMF production once it offers several advantages such as high stability, conversion and yields for HMF as well as high solubility for C6 sugars.5-14 For instance, by using Amberlyst-15 as catalyst, Kannan and Sampath reported the fructose dehydration into HMF using DMF and DMSO as reaction medium.25 It was demonstrated that the catalyst is deactivated in DMF after just four reaction cycles due to the formation of ammonium ions in the acidic medium, which decreased the concentration of acid sites and increased the solution pH. On the other hand, even after seven reaction cycles using DMSO as solvent, both the pH and yield remained constant. Satsuma and co-workers also demonstrated by near-infrared analysis that DMSO underwent a replacement process with adsorbed water on the catalyst, further increasing its activity for fructose dehydration.26 In order to achieve milder conditions, without the use of high boiling point solvents (DMSO, DMA, DMF, and ionic liquids), alcohols have also been proposed as alternative solvents for the synthesis of HMF and its ether derivatives.27 In this context, Brown and co-workers reported the use of several linear alcohols to produce HMF from D-Fructose.28 Despite this green initiative, only low to moderate yields were achieved (19-55%) due the formation of high amounts of HMF-ethers. Cui and co-workers assessed inorganic salts as catalysts (LiCl, CuCl2, NaCl, FeCl2, NH4NO3, etc) to form HMF from D-Fructose using i-propanol (i-PrOH) as solvent.29 Jérôme and


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co-workers disclosed the synthesis of HMF with high purity (95%) using glycerol/ionic liquids as a solvent system from D-Fructose and inulin.30 Alcohols were also used in the presence of DMSO as co-solvent using graphene oxide as solid acid catalyst by Zhu and co-workers.31 Lai and Zhang also explored this more attractive process using homo- and heterogeneous catalyst.32 We have noted that in the majority of the studies, several parameters such as temperature, reaction time, solvent/co-solvent, catalyst loading, concentration and flow rate (in the case of continuous flow processes) have been evaluated individually in order to achieve the highest sugar conversion, selectivity and yield for HMF. However, studies aimed at evaluating the synergy among the factors involved in the HMF synthesis by a multivariate analysis are scarce. The statistical concept of design of experiments (DoE) has been demonstrated to be a powerful tool for identifying important parameters in order to optimize chemical processes, whether in the industrial or academic fields.33 For HMF synthesis, Yang and Li employed a Response Surface Methodology (RSM) to optimize the fructose and glucose dehydration into HMF using a prolinederived ionic liquid (ProCl) as both solvent and catalyst.34 Pereira and co-workers also explored this more convenient and efficient approach for the conversion of glucose into HMF.35 In this study, a Central Composite Design (CCD) was used to assess the most important factors for the reaction. Notably, in neither studies there was a requirement for exhaustive tests for each factor (univariate analysis) to determine the optimum condition, as commonly described in most studies for HMF formation reported so far.5-14 In this context, we report herein a comprehensive investigation of the factors (temperature, reaction time, solvent/co-solvent and catalyst loading) involved in the synthesis of HMF from DFructose by DoE in both batch and continuous flow conditions, using Amberlyst-15 as solid-acid catalyst and alcohols as reaction solvent in the presence of DMSO as co-solvent. In addition, all


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the possible by-products formed from reaction between alcohols and HMF was prepared to access the real selectivity of reaction. In the flow process, a FTIR spectrophotometer was placed after the fixed-bed reactor, allowing in-line monitoring of the process in order to assess catalyst stability, recyclability and process robustness. EXPERIMENTAL SECTION. General procedure for batch reactions. The batch reactions were performed in a sealed tube with magnetic stirrer containing 0.45 g of D-Fructose (0.25 mmol) and 5 mL of a i-PrOH/DMSO solution ranging from 3 to 15% v/v; Amberlyst-15 loading ranged from 10 to 30 mol%; reaction time between 1 to 4 hours and temperature between 80 to 120 °C, as depicted in Table 1. After reaction completion, i-PrOH was removed and the residue obtained was dissolved in water (1 mL). Subsequently, the aqueous phase was extracted with ethyl acetate (5 x 5 mL) and 1,3,5trimethoxybenzene was added to the combined organic layers. Solvent was removed under reduced pressure and the products/by-products (HMF and i-PMF) were quantified by quantitative 1H NMR analysis. General procedure for continuous flow experiments. The continuous flow reactions were performed on a FlowSyn equipment (UNIQSIS). In a 100 mL round-bottomed flask containing a magnetic stirrer were added 2.25 g of D-Fructose and 50 mL of a i-PrOH/DMSO solution (15% v/v), and the resulting suspension was heated at 60 °C to dissolve the D-Fructose. A glass column (10 mm i.d. × 50.0 mm length) was packed with solid catalyst Amberlyst-15 (2.0 g, void volume ca. 2.8 mL). The flow rate was ranged from 0.75 to 0.25 mL.min-1 and temperature from 80 to 110 °C depending on the conditions under evaluation, as depicted in Table 2. The packed column was heated (120 °C) and flushed with i-PrOH/DMSO solution (15% v/v) over 30 minutes before the direct pumping of the D-Fructose solution through the system. A 5 bar back-


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pressure regulator was placed after the fixed-bed reactor to avoid i-PrOH evaporation. Samples were taken after three residence times to ensure steady-state operation. Samples of 10 mL were collected and 1,3,5-trimethoxybenzene was added as internal standard. The resulting solution was concentrated under reduced pressure and the reaction mixture was subjected to 1H NMR analysis. By-products Synthesis. Experimental details in Supporting Information. Flow micro reactor coupled to the FTIR device for in line monitoring. Experimental details in Supporting Information. RESULTS AND DISCUSSION. Preliminary assays in batch: evaluating solvents and by-products formation. Considering the benefits of using alcohol as the solvent, as well as DMSO as a co-solvent due to the several advantages already highlighted in the previous section, their use in both batch and continuous flow conditions was considered here. For the catalyst, a heterogeneous system was chosen, taking into account its unique characteristic over homogeneous systems, such as recyclability in a straightforward manner, which would be crucial for the development of a greener process for industrial scale. Bearing this in mind, commercially available solid acid catalyst Amberlyst-15 was chosen.36 Amberlyst-15 is a macroreticular polymer resin based on cross-linked styrenedivinylbenzene copolymers, and contains macroporous SO3H-functional groups. This solid catalyst is a well-studied resin and regularly used in several industrial processes.37 According to the literature, the solid-acid SO3H-based catalyst is one of the most acidic sites used for HMF synthesis.21,38,39


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In our preliminary experiments, D-Fructose (1) (90 g.L-1) was dehydrated into HMF using a series of alcohols as reaction medium and, in some cases, using DMSO or acetone as co-solvents in the presence of Amberlyst-15. These preliminary assays were performed in order to briefly assess the effect of different solvents on the yield and selectivity for HMF. The HMF-ether byproduct formed from different alcohols was also verified in these initial experiments. A detailed discussion about the preliminary experiments can be found in Table S1 on electronic supplementary information (ESI). After this initial investigation, we have found that in our case, the best solvent system for HMF synthesis would be a i-PrOH/DMSO mixture, exhibiting superior yield (66%) and selectivity. These results are in perfect agreement with recent studies employing common alcohols as reaction media such as MeOH, EtOH, i-PrOH and t- or n-butanol (which provided the highest yield and selectivity using i-PrOH).28,29,31,32 Although i-PrOH proved to be a suitable solvent for HMF synthesis, as well as an effective green solvent, side reactions such as ketal formation and O-alkylations took place, leading to undesirable by-products as described by Lai and Zhang.32 Since 1982, when Brown and co-workers reported the use of alcohols as reaction solvent,28 no study demonstrated the synthesis of these by-products in order to understand and prevent their formation to increase the selectivity to HMF. In this context, three different by-products could potentially be formed using i-PrOH as reaction media, and since these by-products have never been properly synthesized and characterized, we decided to prepare these compounds from HMF in order to assess their formation by 1H NMR and GC-MS analyses of the crude reaction mixture. The synthetic strategy aiming at the preparation of these by-products is outlined in Scheme 2.


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Scheme 2. Synthesis of the potential by-products formed during D-fructose dehydration using iPrOH as solvent. Among the by-products, i-PMF (3) was isolated with 20% yield from the crude reaction mixture after the conversion of D-fructose into HMF in the presence of Amberlyst-15 using iPrOH at 120 °C (Table S1, entry 5). Next, by-product 4 (i-PMF-acetal) was prepared in 98% yield upon ketalization of the carbonyl group of compound 3 in the presence of a water-trapping agent (triisopropyl orthoformate) in anhydrous i-PrOH containing Amberlyst-15. Note that the use of a water-trapping agent was fundamental to the success of this synthesis, since it release iPrOH molecules upon reaction with water formed in the ketalization reaction, avoiding the return of by-product 4 to the aldehyde 3 by hydrolysis. Finally, esterification of the hydroxyl group of HMF with pivaloyl chloride followed by ketal formation, using similar conditions applied to compound 4, and final deprotection using sodium hydroxide afforded the desired HMF-acetal (7) by-product with 50% overall yield (for the 2 steps). In order to check the origin of the by-products 3, 4 and 7 during HMF synthesis from DFructose, control experiments were performed to demonstrate whether they were formed during the D-Fructose dehydration process or by nucleophilic substitution or addition reactions of iPrOH with the recently formed HMF. In this case, pure HMF was exposed to the same


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conditions reported for fructose dehydration (Table S1, entry 5). It was observed that only traces of by-product 3 (i-PMF) was formed in the process, even after 2 days of reaction, indicating that by-products 3, 4 and 7 might be formed by reactions of i-PrOH with the intermediates involved during the D-fructose dehydration process to generate HMF. It is worth mentioning that specific conditions were required for the synthesis of the ketal by-products 4 and 7. Ketals are unstable compounds under aqueous acidic conditions and are rapidly hydrolyzed to the respective aldehydes or ketones. Bearing in mind that the fructose dehydration process involves acidic conditions and releases three molecules of water per molecule of fructose, it is unlikely that these undesirable by-products (4 and 7) are formed under the conditions used here for HMF formation, as has been controversially described in the literature.32 The proper evaluation of by-product formation will be discussed later. Full factorial design for the acid-catalyzed dehydration of D-Fructose in batch. After a preliminary investigation on the by-products formation in the reaction medium, batch and continuous flow reactions were evaluated by DoE. This important statistical tool was used to assess the influence of the parameters involved in the reaction without the requirement of exhaustive experiments (univariate) as commonly described in the literature.5-14 For that, DesignExpert® software (version 9) was used and four independent factors were evaluated in the batch condition, viz. temperature, time, catalyst loading and amount of DMSO in i-PrOH. The factor levels and the obtained responses are described in Table 1. Note that only the i-PMF by-product (3) is described, since our preliminary experiments showed that it is the main by-product generated in the reaction media, in agreement with literature.28,32


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Table 1. Experiment conditions and responses of the 24 full factorial design for the study of acidcatalyzed dehydration of D-Fructose in batch.[a]

Entry

Factor 1

Factor 2

Response 1

Response 2

Temp. (°C)

DMSO (%v/v)

HMF (%) (2)[b]

i-PMF (%) (3)[b]

1

80

3

10

1

14.5

0.8

2

120

3

10

1

40.5

1.15

3

80

15

10

1

10

0.35

4

120

15

10

1

55

0.7

5

80

3

30

1

16.5

0.8

6

120

3

30

1

55

4.5

7

80

15

30

1

28

0.8

8

120

15

30

1

65

1.25

9

80

3

10

4

25

0.7

10

120

3

10

4

58.5

5

11

80

15

10

4

35.5

0.55

12

120

15

10

4

67

1.25

13

80

3

30

4

35

1

14

120

3

30

4

55

11.5

15

80

15

30

4

48

0.6

16[c]

120

15

30

4

71

4

17[d]

100

9

20

2.5

55

1.5

[d]

100

9

20

2.5

53

1

19[d]

100

9

20

2.5

52

1

18

Factor 3 Catalyst (mol%)

Factor 4 Time (h)

[a]

Conditions: 0.45 g of D-Fructose was dissolved in 5 mL of i-PrOH/DMSO. [b] The yields were determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard. [c] Complete conversion for D-fructose was observed by 1H NMR analysis of the reaction mixture using D2O. [d] Center points.


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As presented in Table 1, the highest yield for HMF was obtained under conditions shown in entry 16, in which the maximum of each factor was combined to achieve 71% yield for HMF (response 1) along with 4% of i-PMF as by-product (response 2). In an initial evaluation, all the factors seem to be important for the reaction since their maximum value was required for highest HMF yield. In agreement with this observation, recent studies have demonstrated that the use of high temperature, high percentage of DMSO, long reaction time and high amount of catalyst loading is advantageous for HMF synthesis.5-14 For instance, Pereira and co-workers demonstrated that high temperature is an important and key factor for the dehydration reaction of glucose in the HMF process.35 Probably, the influence of the temperature could be attributed to the considerable activation energy required for fructose dehydration into HMF using solid SO3Hacid functionalized catalyst (55 - 80 kJ.mol-1),38 which is our case. Note, however, that the temperature for the process cannot exceed 120 °C, since Amberlyst-15 is not stable above this maximum. Note also that higher catalyst loading was beneficial to the process. Nevertheless, some care should be taken mainly because some studies have shown that increasing the amount of catalyst can accelerate the rehydration, thus promoting HMF poly-condensation due to the high water-content of the catalyst, as well as mass transfer limitations for the process in heterogeneous conditions.26,39 Also in agreement with recent studies, higher amounts of DMSO were positive for both yield and selectivity of the reaction.25,40 On this subject, Vlachos and coworkers showed by molecular dynamics investigation that there is a strong interaction between DMSO and HMF, which restricts the contact with water and prevents both HMF polycondensation and formation of levulinic and formic acids.40


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Aiming at evaluating the effects of the factors and their possible interactions, the half-normal probability plot is presented in Figure 1.

Figure 1. Half normal probability plot of standardized effects in batch process. In the half-normal probability plot, the red line indicates the place where the points must fall if the effects were zero, whereas significant effects have a label and fall toward the right side of the line. Therefore, as our preliminary analysis indicated, temperature, catalyst, DMSO, and reaction time are significant and directly related with high yields for the reaction. Note also that there is no interaction among the factors, and consequently, there is no requirement for a multivariate analysis to improve the HMF yield. Figure 1 also indicates that temperature is the most important factor and the percent contribution of temperature for the process evaluated by DoE is 66.2%, followed by time (12.58%), DMSO (6.35%) and catalyst (4.56%) (Table S2).


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After the important factors were identified, a linear model was developed relating the four factors ( , , , and ) with the yield (y), as demonstrated in Eq 1. The confidence intervals for each coefficient in the linear model are presented in the ESI (Table S3). The validity of the model can be evaluated based on the analysis of variance (ANOVA) as demonstrated in Table S4 in the ESI.

= + + + + [. 1] In the analysis of variance for the linear model, as shown in Table S4, the F-Value of 30.63 implies that the model is significant and some factors represent a significant effect, since it is higher than the F-tabulated (F4,14, confidence level 95%). Lack of fit also indicates whether the proposed model represents the experimental data well. As Table S4 shows, the linear model is not well adjusted to our data (considering 95% confidence level) since the F-value is slightly superior to the F-Tabulated (F12,2). Another important aspect is the p-value for the factors, which should be less than 0.05 to be significant (considering 95% confidence level). In this case A, B, C, and D are significant model terms, as indicated in Table S4. Figure 2 shows the 3D surface plot, which provides a graphical representation of the relation between two independent factors and the response (HMF yield). As can be seen, the center point is above the surface, corroborating with the lack of fit observed in the ANOVA. This fact indicates that a quadratic model might be necessary to properly describe the center of the experimental domain. However, it is possible to evaluate the general trends of the response according to the variation of the factors using the linear surfaces shown in Figure 2.


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Figure 2. The 3D surface plot for the factors for the dehydration reaction of D-fructose into HMF in batch: (A) Yield vs DMSO, Temperature; (B) Yield vs Time, Temperature; (C) Yield vs Catalyst, Temperature; (D) Yield vs Catalyst, DMSO; (E) Yield vs Time, DMSO and; (F) Yield vs Catalyst, Time. The high influence which temperature imposes on the reaction process is clearly observed in Figure 2. Note the pronounced inclination of the response surface edge related to temperature


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(Figure A, B, and C). Moreover, through the visual inspection of these graphs, all factors should be kept in their highest levels in order to obtain higher yields (>71%), mainly temperature (120 °C), time (4 h) and DMSO (15%), as Table 1, entry 16 indicated. Indeed, it should be noted that using the aforementioned i-PrOH/DMSO ratio, both yield and selectivity of the reaction were improved. Corroborating these results, Zhang and Lai showed maximum HMF yield using a more activated Amberlyst-15 and pure i-PrOH as solvent without the use of DMSO as a cosolvent in only 45% along with i-PMF formation of 28%.32 Brown and co-workers also demonstrated high i-PMF formation using only i-PrOH as solvent (i-PMF 45% yield).28 In addition, the mixture i-PrOH/DMSO in 15% v/v has a lower boiling point (86.2 °C, determined by ASPEN Plus, v8.8 software) when compared to a recent study employing 1,4-dioxane/DMSO (110 °C) as solvent for HMF production in flow regime.19 These results and comparisons confirm the importance of using DMSO as a co-solvent as well as our system as an attractive green solvent. Regarding the by-product formation, Figure S1 in the ESI shows the 3D surface plot for the second response (i-PMF). Notable changes are observed in the graphs when the amount of DMSO is varied as a function of the temperature, catalyst or time, demonstrating their importance to avoid the formation of i-PMF as by-product. In general, it can be pointed out that the yield of 71% is the maximum for these conditions in batch inside the experimental domain studied. It is important to highlight that it is not interesting to increase the levels of the factors any further, since Amberlyst-15 is unstable above 120 °C, and higher reaction times and amounts of DMSO would be unattractive to a practical sustainable process. For this reason, we decided to evaluate this process under continuous flow conditions and the results are presented in the next section.


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Full factorial design for the acid-catalyzed dehydration of D-Fructose in continuous flow regime. In this part of the study, we turned our attention to continuous flow regime, which has been shown to offer several advantages over the batch mode, even for HMF synthesis.19-24 For the DoE, the two most important factors described in batch were chosen, that is, temperature and time (residence time). The amount of DMSO was kept at the optimal ratio observed in the batch reactions (15% v/v), once lower or higher amounts are not desirable due to aspects already discussed. Since the Amberlyst-15 catalyst showed poor influence on the HMF yields, this factor was also fixed. To determine the range of flow rate for the DoE, a FTIR flow cell containing an ATR-based probe (FlowIR) was placed at the outlet of the fixed-bed reactor, and the conversion of D-fructose into HMF was monitored in-line by varying the flow rate from 2.0 to 0.25 mL.min1

(Figure S2, ESI). Thus, the limits of the flow rate factor were set in a range of 0.75 to 0.25

mL.min-1 due to the higher conversion of D-fructose into HMF in this range. In view of the reduced number of factors, a full factorial design 22 would give us only five experiments with one center point. Therefore, a duplicate full factorial design 22 was planned to access nine experiments in order to improve the statistical analysis (Table 2).


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Table 2. Duplicate full factorial design 22 for acid-catalyzed dehydration of D-Fructose in continuous flow regime.[a]

Entry

Factor 1

Factor 2

Response 1

Response 2

Temp. °C

Flow rate mL.min-1

HMF[b] (%)

i-PMF[b] (%)

1

80

0.25

83

0.7

2[c]

110

0.25

95

5

3

80

0.75

60

0

4

110

0.75

90

2

5

80

0.25

84

0.6

6[c]

110

0.25

95

5

7

80

0.75

63

0

8

110

0.75

92

2

9[d]

90

0.50

84

1.6

[a]

Conditions: For each experiment, 2.25 g of D-Fructose were dissolved in 50 mL of i-PrOH/DMSO 15% v/v. [b] Yields were determined by 1H NMR analysis using 1,3,5trimethoxybenzene as internal standard. [c] Complete conversion for D-fructose was observed by 1H NMR analysis of the reaction mixture using D2O. [d] Center point.

Similarly, as observed in batch, high temperature is also advantageous for the continuous flow process, as well as lower flow rates (Table 2). Note that when the factors are inversely varied (high temperature associated with low flow rate), highest yields are obtained (up to 95%). In addition, low amounts of the by-product i-PMF (3) were obtained in all experiments (0-5%). The significance of the factors, as well as their interaction can be better evaluated observing the halfnormal probability plot for the continuous flow process presented in Figure 3. As for the batch process, the percent contribution of the variables is shown in Table S5 in the ESI.


19


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Figure 3. Half normal probability plot of standardized effects for the continuous flow process.

In the half-normal plot (Figure 3), both factors are significant and temperature represents 63% of contribution, while the flow rate 25%, and the interaction between the factors (AB) 12% (Table S5). Based on the half-normal plot and the percentage of the contribution (Figure 3 and Table S5), temperature is the most important factor for the continuous flow process, as observed in the batch reaction. As can be seen in Table S5 (ESI), temperature has a positive effect (therefore it should be increased to enhance the yield) whereas the flow rate has a negative effect (it should be lowered to increase the yield). Table S6 (ESI) shows the confidence intervals for each factor, and below, the equation of the linear model is presented:

= + + [. 2]


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To assess the magnitude of the experimental error and the validity of the linear model, we carried out the Analysis of Variance (Table S7, ESI). The F-Value of 266.32 suggests that the model is highly significant by comparison with the F-Tabulated (F3,5, confidence level 95%). The F-test for lack of fit indicated that the linear model is suitable for representing the experimental data, since F-value is lower than F-tabulated. Also in the ESI, Figure S3 shows a complete array of diagnostic graphs for the linear model. These graphs are complementary to the ANOVA and corroborate the validity of the proposed model to describe the continuous flow process. The relation between temperature and flow rate in function of HMF is presented in the 3D surface plot (Figure 4).

Figure 4. The 3D surface plot for the factors (temperature and flow rate) for the dehydration of D-fructose into HMF under continuous flow conditions.

By visual inspection of Figure 4, it is possible to establish some important considerations for the process. Note that when the flow rate is 0.25 mL.min-1, the temperature does not exert as much influence on the reaction yield, and only a slight inclination on the HMF yield axis is observed ranging from 80 to 110 °C. In sharp contrast, an accentuated variation in the HMF yield axis is observed when temperature is varied using the flow rate of 0.75 mL.min-1. This fact


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proves the significance of the interaction between the factors. It can also be seen in the surface that the variation of HMF yield at the temperature of 110 °C in different flow rates (from 0.75 to 0.25 mL.min-1) is negligible, therefore a low flow rate along with a high temperature is recommended. This combination can provide HMF in up to 95% yield (Table 2). As demonstrated by the DoE, a low flow rate increases the conversion rate of D-fructose into HMF, providing better yields due to the higher contact between D-fructose/catalyst in the continuous flow process. However, note that this factor must be accurately adjusted to avoid high contact between recently formed HMF and the high water-content in the cavity of the Amberlyst catalyst (12 mmol.g-1),26 which would lead to side reactions. In most of the studies using continuous flow conditions to prepare HMF, low flow rates were used to achieve the best results. For instance, Hermans and Aellig used a flow rate of 0.14 mL.min-1 to achieve 92% yield from D-fructose17, and Afonso and co-workers applied a flow rate of 0.3 mL.min-1 to obtain 90% yield also from D-fructose.24 Since the amount of DMSO and catalyst loading were already set, the factors addressed by the model could be more precisely refined to further improve the HMF yield and/or selectivity. However, as emphasized here, the Amberlyst-15 resin used as catalyst has a maximum working temperature of 120 °C. For the residence time, decreasing the flow rate would lead to a lower space-time-yield for HMF production, whereas a shorter residence time would lead to a lower conversion and HMF production, which would be undesirable for an industrial scale production. Bearing this in mind, we set a flow rate of 0.25 ml.min-1 at 110 °C as the best conditions for these factors for HMF production under continuous flow conditions. Notably, under this condition, HMF was produced in 95% yield in just 11.2 minutes of residence time (Table 2).41 Note that the second response was not properly evaluated in this study, since


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the amount of i-PMF formed in the reaction medium was not a limited response, presenting acceptable values for the proposed study (only up to 5%). Evaluation of by-product formation in batch and continuous flow regime. After having synthesized the possible by-products formed during the dehydration reaction of fructose into HMF using i-PrOH (Scheme 2), we addressed their actual formation during the process by analytical techniques. In that way, the crude mixture from the optimum reaction conditions for both batch (71% yield) and continuous flow regime (95% yield) were analyzed by 1H NMR. As presented in Figure 5, formation of the by-products 4 and 7, as pointed out by Lai and Zhang using similar conditions without the use of DMSO,32 was not detected by 1H NMR analysis. GCMS was also used to analyze the reaction mixture mainly from the continuous flow process to confirm the high selectivity and yield achieved in this system. GC-MS spectra in the Figures S4S7 (ESI) also confirm the formation of by-product 3. Note that the by-products 4 and 7 could not be detected in the crude reaction.


23


HO H2 C

O O 2

O H2 C

O O 3

O H2 C

O O O 4

Page 24 of 34

HO H 2C

O O O 7

Figure 5. Expanded region for methylene groups in the 1H NMR spectra for all possible byproducts in comparison to HMF: (A) 1H NMR spectrum of HMF-acetal (7);42 (B) 1H NMR spectrum of i-PMF-acetal (4); (C) 1H NMR spectrum of i-PMF (3); (D) 1H NMR spectrum of HMF obtained under continuous flow regime (0.25 mL.min-1 at 110 °C; crude); (E) 1H NMR spectrum of batch condition (120 °C, 4 h; crude) and; (F) 1H NMR spectrum of standard HMF (Aldrich).

The signals corresponding to the methylene hydrogens for each compound were used to assess reaction selectivity. In Figure 5, the expansions A, B and C of the 1H NMR spectra are correlated to the by-products 7, 4 and 3, respectively. Expansions D, E and F correspond to HMF prepared under continuous flow regime (entry 6, Table 2), HMF obtained in batch (entry 16, Table 1), and standard HMF obtained from a commercial source, respectively. Note that the crude reaction spectra from continuous and batch conditions (D and E) present only the


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methylene group of i-PMF by-product (3), without any traces of the by-products 4 and 7. Similar formation of the by-product 3 was experimentally shown for batch and continuous flow reactions (ca. 5%). However, 4 hours were necessary for full D-Fructose consumption in batch, affording HMF in 71% yield, when on the other hand, a short residence time (11.2 min) produced HMF in up to 95% yield, with total sugar conversion in continuous flow regime. In addition, the spacetime-yield is 14 times higher for continuous flow conditions than batch,43 representing the highest yield and selectivity for HMF production under continuous flow conditions reported so far.19-24 In-line FTIR monitoring: evaluating catalyst recyclability and process robustness in continuous flow regime. In order to evaluate catalyst recyclability and process robustness, a long-term experiment for the production of HMF was planned, and for this purpose, a FTIR flow cell containing an ATR-based probe (FlowIR) was connected to the outlet of the fixed-bed reactor for real-time monitoring (Figure S8, ESI). FTIR-based in-line monitoring offers a suitable and versatile analytical tool for continuous flow chemical processing, and several studies have demonstrated its successful application.44 For the monitoring of HMF formation under continuous flow regime, the band at 1.680 cm-1 of the carbonyl group stretching in the HMF product, and the band at 1.083 cm-1 assigned to the CO stretching of D-Fructose were selected for in-line monitoring (Figures S9 and S10). For the monitoring setup, the column outlet solution was pumped through the ATR-based probe and, eventually, samples were taken and analyzed by 1H NMR in order to correlate conversion and yield with the ConcIRT trends profile.45 Figure 6 shows the ConcIRT trends profile during the reaction progress for the first 8 hours of monitoring with the FlowIR device.46 This process was


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repeated for 5 days using the same column filled with Amberlyst-15 and the same trend was observed (Figure S11, ESI). HO

Amberlyst-15

O OH

HO HO

OH

HO 2g

∆

BPR

FTIR

O O

D-Fructose ( 1) in i-PrOH/DMSO

O O

5.0 bar HMF (2 )

O

+ i-PMF (3 )

Figure 6. ConcIRT trends profile of HMF production under continuous flow conditions during 8 hours of monitoring.

The FTIR in-line monitoring showed excellent stability of the catalyst, as well as complete conversion of D-fructose and high HMF formation. At a flow rate of 0.25 mL.min-1 and 110 °C, which are our optimal conditions, HMF was continuously produced during 8 hours a day, 5 days a week (40 hours), with an average yield of 95% with total sugar conversion (Figure S11). Over a total of 40 h, 27 g of D-Fructose was processed, producing 19 g of HMF in 95% yield, which would correspond to a D-fructose/catalyst ratio of 6 mol%.36 The FlowIR device providing the actual ConcIRT spectrum from the reaction solution, it thereby enables to monitor the reaction progress. In this context, comparison between the reference ConcIRT spectra (D-Fructose and HMF) and the real-time ConcIRT spectrum reported


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by the FlowIR device should determine the D-Fructose conversion. In that way, Figure 7 shows the reference spectra for HMF and D-Fructose overlapping with the actual ConcIRT spectrum of the crude reaction mixture under continuous flow regime at a flow rate of 0.25 mL.min-1 at 110°C.

Figure 7. ConcIRT spectra of HMF (green line), D-Fructose (red line) and the crude reaction mixture at 0.25 mL.min-1 flow rate and 110 °C (blue line).

As can be seen, there is a great similarity between the ConcIRT spectrum for the HMF product (green line) and the spectrum generated from the reaction stream (blue line) at 0.25 mL.min-1 and 110 °C. The characteristic HMF stretching bands at 1680 and 1523 cm-1 are unequivocally found in the crude reaction spectrum. The broad band at 3250 cm-1 is due to the presence of water generated during the dehydration process (O-H stretching). The D-Fructose bands, such as the intense band at 1083 cm-1 (Figure S9), did not appear in the crude reaction spectrum, which corroborates the total sugar conversion.


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CONCLUSIONS When carefully evaluated, and by using a co-solvent, alcohols such as i-PrOH offer an effective green solvent for HMF synthesis. We have shown that HMF could be produced in batch with 71% yield, whereas under continuous flow conditions, HMF was produced in up to 95% yield with total sugar conversion. A long-term in-line monitoring by the coupling of a FTIR device to the continuous flow micro reactor was also reported for the first time. This coupling has given us valuable insights into the events occurring throughout the process, such as assessing the long-time stability of the catalyst Amberlyst-15, that worked at 110 °C by 5 days (40 hours). Correspondingly, there was no significant change that could compromise the HMF yield and selectivity. We have also shown that HMF-ethers/ketals by-products, such as i-PMF-acetal (4) and HMF-acetal (7) - which have been synthesized and analyzed by 1H NMR and GC-MS for the purpose of this work - are not formed in either batch or continuous flow regime. Using the statistic tool Design of Experiments, we evaluated the main factors and determined their real contributions to this process in batch and continuous flow regime. For both processes, temperature was found the most important factor, since it was directly related to high yields. In addition, analysis of variance (ANOVA), diagnostic graphs and response surface plots allowed the evaluation of the linear model, as well as a thorough understanding of the system

SUPPORTING INFORMATION In the Supporting Information can be found NMR, GC-MS, and FTIR spectra, details about the initial screening using alcohols as solvent, byproduct synthesis, continuous flow experiment, design of experiments, and in-line reaction monitoring.


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ACKNOWLEDGMENT The authors gratefully acknowledge financial support from the São Paulo Research Foundation – FAPESP (awards No. 2006/57897-9, 2014/26378-2 and 2014/25770-6), CNPq (award No. 453862/2014-4) and CAPES (R.G.). We are also thankful to the Obesity and Comorbidities Research Center – OCRC (FAPESP Award No. 2013/07607-8) for providing us with the UNIQSIS flow system used in this work, and to Fabio Batista Ferreira from Mettler Toledo for his support with FTIR devices. The authors are also grateful to Prof. Dr. José Augusto Rosário Rodrigues (Institute of Chemistry/UNICAMP) and Prof. Dr. José Luiz de Paiva (School of Chemical Engineering/USP) for lending us the ReactIR 45 and the DS Micro Flow Cell, respectively. Finally, special thanks go to Prof. Dr. Roy Edward Bruns (Institute of Chemistry/UNICAMP) for helpful discussions concerning the design of experiments data.

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Lia, Y.; Liua, H.; Songa, C.; Gua, X.; Lia, H.; Zhua, W.; Yina, S.; Han, C.; The dehydration of fructose to 5-hydroxymethylfurfural efficiently catalyzed by acidic ionexchange resin in ionic liquid. Bioresource Technol, 2013, 133, 347. Mushrif, S. H.; Caratzoulas, S.; Vlachos, D. G. Understanding solvent effects in the selective conversion of fructose to 5-hydroxymethyl-furfural: a molecular dynamics investigation. Phys. Chem. Chem. Phys., 2012, 14, 2637-2644. Residence time was calculated as follow: V. reactor / Flow rate The NMR analysis of by-product 7 required anhydrous CDCl3 to avoid ketal decomposition. Note that a duplicate signal for methylene group is observed due to its coupling with hydroxyl group. Space-time yield = g (amount of HMF) / [V (reactor) x t (time)]. Same formula for both batch and continuous conditions. Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L. ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing. Org. Process Res. Dev, 2010, 14, 393-404. ConcIRT is a chemometric treatment based on curve resolution that provides a concentration profile (component) and calculates the spectra (ConcIRT spectrum profile) of a specific compound or a product formed during the reaction process. To generate this graphic, the solvent ConcIRT spectrum (i-PrOH/DMSO 15% v/v) was removed.


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For Table of Contents Use Only Graphical Abstract Synthesis of an important bio-based chemical, 5-(hydroxymethyl)furfural, was evaluated by DoE in both batch and flow regimes using alcohols as solvent, heterogeneous catalyst and FTIR in-line monitoring.


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Conversion of d-Fructose to 5-(Hydroxymethyl)furfural: Evaluating

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