Laboratory Experiment pubs.acs.org/jchemeduc
Batch and Flow Synthesis of 5‑Hydroxymethylfurfural (HMF) from Fructose as a Bioplatform Intermediate: An Experiment for the Organic or Analytical Laboratory Svilen P. Simeonov and Carlos A. M. Afonso* Research Institute for Medicines and Pharmaceuticals Sciences, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal S Supporting Information *
ABSTRACT: In this laboratory experiment students synthesize 5-hydroxymethylfurfural (HMF) by dehydration of fructose in either batch or flow chemistry conditions. Tetraethylammonium bromide (TEAB) was used as reaction medium with acidic Amberlyst 15 as heterogeneous catalyst in batch conditions or 5% H2SO4 homogeneous catalysis in flow conditions. Isolation of HMF was achieved by simple precipitation and filtration of TEAB. HMF was isolated in up to 97% yield and 98% purity in batch and 77% yield and 92% purity in flow conditions. Reaction media and catalyst were recycled.
KEYWORDS: Upper-Division Undergraduate, Analytical Chemistry, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Alcohols, Carbohydrates, Green Chemistry, Catalysis, Industrial Chemistry
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Scheme 1. Possible Chemical Building Blocks Derived from HMF
iminishing natural resources and their growing prices opened a new space for research on the synthesis of new molecules derived from biorenewable resources that can serve as energy sources1 or chemical intermediates.2,3 Among the already reported large number of chemical building blocks and intermediates accessible from biorenewable resources4 derived from carbohydrates, 5-hydroxymethylfurfural (HMF) has been described as one of the most promising for industry,5 and a number of its possible applications and transformations, such as production of biofuel 2,5-dimethylfuran, as well as chemical building blocks for the polymer industry, such as furan-2,5dicarboxylic acid and furan-2,5-dicarbaldehyde, have been reported (Scheme 1).6 HMF is synthesized mainly by the dehydration of monosaccharides, requiring the loss of three water molecules. Disaccharides or polysaccharides, such as sucrose, cellobiose, inulin, or cellulose, can be used as starting materials, but hydrolysis is necessary for depolymerization. The process is usually acid catalyzed, and fructose is observed to be the best starting material.7 Nevertheless, glucose is more desirable as a starting material because it is the most abundant monosaccharide in nature. Unfortunately, glucose is much less reactive because it is in the form of a more stable six-member ring compared to the five-member ring for fructose, and normally the formation of HMF from glucose requires its initial isomerization to fructose. Several problems limit the production of HMF at industrial scales. Probably the major problem is the isolation of HMF.6 Because of the low solubility of carbohydrates in organic © XXXX American Chemical Society and Division of Chemical Education, Inc.
solvents, water or biphasic systems water/organic solvent are widely studied as reaction media, but HMF is difficult to extract because the distribution coefficient between organic and aqueous phases is not favorable.5 This problem has been partially overcome by using more efficient extracting solvents, such as methyl isobutyl ketone (MIBK).8,9 Continuous extraction procedures have also been applied.10 Even though improvements in this field have been achieved in the past few
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dx.doi.org/10.1021/ed300780h | J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
years, more effective and industrially applicable isolation techniques still need to be developed. A batch method for the synthesis of HMF from fructose by using resin acid catalysis and precipitation of the reaction media was developed as a student laboratory experiment. Students are introduced to an important transformation reaction for the biorefinery, applying an innovative and recyclable approach. The main goal is to illustrate a simple and industrially useful separation technology that may open a new opportunity for higher-scale production of HMF (Scheme 2).11 This experi-
Scheme 3. Fructose Dehydration to HMF Using Amberlyst 15 as Catalyst
15 were separated from the HMF via workup with ethanol and ethyl acetate. Evaporation of ethyl acetate/ethanol gave the product. TEAB and Amberlyst 15 may be reused several times. Details of the procedure and analysis (HPLC and NMR) are provided in the Supporting Information. A flow process experiment for the synthesis of HMF from fructose using 5% H2SO4 as catalyst under homogeneous conditions was developed for the student laboratory. A standard glass column for flash chromatography was connected to an in-house-made glass reactor (internal diameter, 4 mm; internal volume, 13 mL; length, 1.02 m), which was placed in a boiling water bath. A round-bottom flask was connected to the flow reactor to collect the product (pictures are available in the Supporting Information). TEAB was mixed with 5% aqueous H2SO4 in a 3:1 ratio, resulting in a homogeneous mixture at room temperature, and was used with fructose in a 12:1 ratio. Flow around 0.5−0.6 mL/min (1 drop per 3−4 s) was controlled by using slight positive air pressure until the reaction in the glass column finished. After the mixture in the feed column was completed, the flow was difficult to control precisely. After the reaction was completed, the sulfuric acid was neutralized with an equimolar amount of NaHCO3, followed by the same isolation process described for the batch reaction. The E-factors of the batch and flow processes were calculated by the students using the following equation:
Scheme 2. Overview of Integrated and Recyclable Approach for HMF Synthesis and Isolation from Carbohydrates
ment provides additional student learning goals, such as more environmentally friendly processes, an involved reaction mechanism, spectroscopic structural elucidation (1H NMR), high purity evaluation (HPLC), and consolidation of general organic chemistry preparative practices. In addition, a flow process for HMF synthesis under homogeneous acid-catalyzed conditions, using, again, precipitation as a quantitatively isolation technology, is described. Synthesis experiments using a flow chemistry approach have been reported,12−14 as well as a kinetic study15 using flow chemistry; a general discussion that compares batch and flow chemistry was published.16 The protocol described here is based on a simple setup readily available in student laboratories, and does not use expensive equipment, such as a microreactor. It is an example of scalable, combined biorefinery−flow technology.
E‐factor = g (waste)/g (product)
The obtained values were used for a discussion on the green chemistry credits of the experiments and comparison of the two catalytic systems used.
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HAZARDS Sulfuric acid is a highly corrosive acid and may cause severe skin and eye burns. Ethyl acetate is flammable and may cause CNS depression on inhalation. Tetraethylammonium bromide (TEAB) is slightly hazardous in the case of skin contact (irritant), eye contact (irritant), and ingestion. HMF can cause eye and skin irritation. It may produce yellow stains on the skin, which are considered harmless. Students should wear protective clothing, gloves, and safety goggles. Acetonitrile and CDCl3 are hazardous in the case of eye contact (irritant), ingestion, and inhalation, and slightly hazardous in the case of skin contact (irritant).
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EXPERIMENT OVERVIEW Upper-division undergraduate students worked either individually or as a team of 2−3 students during one laboratory section (2.5−3 h). Each team runs one experiment, either batch or flow. The obtained results were compared and discussed at the end of the laboratory. In the batch experiment (Scheme 3), fructose was added to tetraethylammonium bromide (TEAB) containing 10% water as a reaction medium and Amberlyst 15 (10% w/w of fructose) as a catalyst. Water was required to suppress the formation of side products. The reaction mixture was heated with stirring to 100 °C using a boiling water bath. After 15 min, the heterogeneous reaction mixture turned homogeneous and the color of the reaction changed from white to brown. Water was removed using a rotary evaporator. Solid TEAB and Amberlyst
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RESULTS AND DISCUSSION The experiment has been run by 10 second-year students in a five-year pharmaceutical science course in groups of 2. In the batch reaction, students obtained HMF yields up to 97% (range 90 to 97%) and 98% purity. For the flow process, 2 groups of students obtained HMF in 77% yield and 92% purity. The purity and characterization of HMF were evaluated by HPLC analysis and 1H and 13C NMR. Formation of 8% side product (by HPLC) from the flow process has been observed resulting B
dx.doi.org/10.1021/ed300780h | J. Chem. Educ. XXXX, XXX, XXX−XXX
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Laboratory Experiment
(8) Lima, S.; Neves, P.; Antunes, M. M.; Pillinger, M.; Ignatyev, N.; Valente, A. A. Conversion of mono/di/polysaccharides into furan compounds using 1-alkyl-3-methylimidazolium ionic liquids. Appl. Catal. A 2009, 363, 93−99. (9) Moreau, C.; Durand, R.; Razigade, S.; Duhamet, J.; Faugeras, P.; Rivalier, P.; Ros, P.; Avignon, G. Dehydration of fructose to 5hydroxymethylfurfural over H-mordenites. Appl. Catal. A 1996, 145, 211−224. (10) Hu, S.; Zhang, Z.; Zhou, Y.; Han, B.; Fan, H.; Li, W.; Song, J.; Xie, Y. Conversion of fructose to 5-hydroxymethylfurfural using ionic liquids prepared from renewable materials. Green Chem. 2008, 10, 1280−1283. (11) Simeonov, S. P.; Coelho, J. A. S.; Afonso, C. A. M. An Integrated Approach for the Production and Isolation of 5-Hydroxymethylfurfural from Carbohydrates. ChemSusChem 2012, 5, 1388−1391. (12) Merino, J. M. A simple, continuous-flow stirred-tank reactor for the demonstration and investigation of oscillating reactions. J. Chem. Educ. 1992, 69, 754−756. (13) Tundo, P.; Rosamilia, A. E.; Aricò, F. Methylation of 2-Naphthol Using Dimethyl Carbonate under Continuous-Flow Gas-Phase Conditions. J. Chem. Educ. 2010, 87, 1233−1235. (14) van Rens, L.; van Dijk, H.; Mulder, J.; Nieuwland, P. Using a Web Application To Conduct and Investigate Syntheses of Methyl Orange Remotely. J. Chem. Educ. 2013, DOI: 10.1021/ed300719q. (15) Lindfors, L.-E. An undergraduate experiment in chemical engineering reactor kinetics. J. Chem. Educ. 1971, 48, 472−473. (16) Englund, S. M. Chemical processingBatch or continuous. Part I. J. Chem. Educ. 1982, 59, 766−768.
in lower HMF purify compared to the batch process. (The spectra and chromatograms are in the Supporting Information.) The execution of this experiment provided the following student learning objectives and assessment for achieving the proposed goals: (a) The batch and flow experiments were performed during the same lab class so a comparison of the results and processes stimulated discussion by students of more environmentally friendly processes by comparison of the Efactor for each process. (b) This experiment exposed students to an acid-catalyzed dehydration mechanism, to NMR for structural analysis, and to general procedures, such as thin-layer chromatography analysis, solvent evaporation, and precipitation.
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CONCLUSIONS Two synthetic approaches for the synthesis of HMF from fructose were developed and implemented for educational purposes. Students were introduced to the synthesis of one important building block derived from biorenewable resources by batch heterogeneous catalysis and flow homogeneous catalysis, followed by isolation as a key separation process commonly used in industry.
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ASSOCIATED CONTENT
S Supporting Information *
Instructions for the students, notes for instructors, spectral and analytical data, pictures of used flow apparatus and students’ results. This material is available via the Internet at http://pubs. acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: carlosafonso@ff.ul.pt. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to Fundaçaõ para a Ciência e a Tecnologia and FEDER (ref. SFRH/BD/67025/2009, PTDC/ QUI-QUI/119823/2010, PEst-OE/SAU/UI4013/2011) for financial support and to secnd year students from pharmaceutical science course (total 5 years) of the Faculty of Pharmacy of University of Lisbon for reproducing those experiments.
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