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WO2024178283A1 - Direct bronsted acid-catalyzed dehydration of glucose to 5-hydroxymethylfurfural - Google Patents

Direct bronsted acid-catalyzed dehydration of glucose to 5-hydroxymethylfurfural Download PDF

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Publication number
WO2024178283A1
WO2024178283A1 PCT/US2024/016994 US2024016994W WO2024178283A1 WO 2024178283 A1 WO2024178283 A1 WO 2024178283A1 US 2024016994 W US2024016994 W US 2024016994W WO 2024178283 A1 WO2024178283 A1 WO 2024178283A1
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Prior art keywords
glucose
aqueous phase
hmf
hydroxymethylfurfural
bronsted acid
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PCT/US2024/016994
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French (fr)
Inventor
Natalia Rodriguez QUIROZ
Dionisios G. Vlachos
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Quiroz Natalia Rodriguez
Vlachos Dionisios G
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Publication of WO2024178283A1 publication Critical patent/WO2024178283A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C13—SUGAR INDUSTRY
    • C13K—SACCHARIDES OBTAINED FROM NATURAL SOURCES OR BY HYDROLYSIS OF NATURALLY OCCURRING DISACCHARIDES, OLIGOSACCHARIDES OR POLYSACCHARIDES
    • C13K1/00—Glucose; Glucose-containing syrups
    • C13K1/02—Glucose; Glucose-containing syrups obtained by saccharification of cellulosic materials

Definitions

  • Glucose is the most abundant monosaccharide in biomass feedstocks. Its efficient valorization is essential for an economically viable transition from the currently prevalent fossil fuels-based to a sustainable chemical industry (Behrens, M. et aL, Catalysis for the Conversion of Biomass and Its Derivatives (e-published 2013); Chheda, J. N. et aL, Angew. Chemie Int. Ed 46, 7164-7183 (2007); Bender, T. A. et aL, Nat. Rev. Chem. 2, 35-46 (2016); Thoma, C. et aL, ChemSusChem 13, 3544-3564 (2020); Van Putten, R.-J. J.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural, comprising the steps of:
  • the starting mixture is a single phase.
  • the starting mixture is a biphase.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural, comprising combining water, glucose, a Bronsted acid catalyst and an organic solvent under reaction conditions sufficient to produce the 5-hydroxyfurfural directly from the glucose.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural, comprising contacting an aqueous phase comprising, consisting essentially of, or consisting of water, glucose, and a Brpnsted acid catalyst with an organic solvent under reaction conditions sufficient to produce the 5-hydroxyfurfural directly from the glucose.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the organic solvent comprises one or more of alcohols, ketones, lactones, or any combination thereof.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the alcohol comprises one or more Cl to C6 straight chain, branched, or cyclic alkyl alcohols.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the alcohol comprises, consists essentially of, or consists of 1-butanol, 2-pentanol, or any combination thereof.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the ketone comprises, consists essentially of, or consists of methyl isobutyl ketone, 2-butanone, 2-pentanone, 4-heptanone, 2-propanone, or any combination thereof.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the organic solvent comprises, consists essentially of, or consists of methyl isobutyl ketone.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the Bronsted acid catalyst comprises, consists essentially of, or consists of hydrochloric acid, sulfuric acid, phosphoric acid, or any combination thereof, preferably hydrochloric acid.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase further comprises a salt, such as an organic salt or an inorganic salt, preferably an inorganic salt.
  • a salt such as an organic salt or an inorganic salt, preferably an inorganic salt.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the salt comprises, consists essentially of, or consists of sodium chloride and/or potassium chloride.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase has a concentration of the salt in a range of about 0.05 M to about 0.25 M.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein a temperature the reaction conditions in (b) include a temperature in a range of about 105 °C to about 145 °C.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the starting mixture comprises about 2% (v/v) to about 10% (v/v), preferably about 2% (v/v) to about 5% (v/v), of the aqueous phase.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein a reaction time under the reaction conditions in (b) is in a range of up to about 300 minutes, preferably about 60 minutes to about 180 minutes.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase has a concentration of the glucose in a range of about 0.05 M to about 0.3 M.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase has a concentration of the Bronsted acid catalyst in a range of about 0.25 M to about 1.0 M.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the glucose is obtained by contacting cellulose with an acidic aqueous solution.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the cellulose that serves as the source of the glucose is obtained from a non-edible lignocellulosic biomass.
  • the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the 5-hydroxymethylfurfural is obtained in at least a 50% yield, preferably in at least a 75% yield based on the amount of glucose starting material.
  • FIG. 1 illustrates how in the present invention, glucose can be directly converted into HMF compared to conventional methods that proceed through a fructose intermediate.
  • FIG. 2a illustrates a schematic representation of a methyl isobutyl ketone (MIBK)-rich system with miscible amounts of the reactive aqueous phase at reaction temperature.
  • FIG. 2b shows glucose conversion and HMF yield in a single MIBK phase reaction with soluble amounts of the aqueous solution (upper squares and circles) and the aqueous phase reaction (lower squares and circles).
  • FIG. 2c shows a HMF selectivity profile (circles) and sugar dimer yield (squares) in the MIBK system. All reactions were run at 125 °C.
  • FIG. 3a illustrates HPLC chromatograms of reaction mixtures after 270 minutes at 125 °C using a RI-410 detector.
  • FIG. 3b illustrates HPLC chromatograms of reaction mixtures after 270 minutes at 125 °C using a UV detector at 254 nm.
  • the most relevant by-product species observed include glucose (G), sugar dimers (disaccharides) (D), formic acid (FA), levulinic acid (LA), HMF and an unidentified byproduct (BP).
  • FIG. 4 illustrates a reaction mechanism for the proton-initiated dimerization of glucose to 1,4 cellobiose.
  • FIG. 5a, FIG. 5b and FIG. 5c illustrate the acetone effect on the yield of HMF in MIBK with increasing aqueous to organic ratios (organic: aqueous) of 1 :0.04 (FIG. 5a); 1 :0.06 (FIG. 5b); and 1:0.08 (FIG. 5c). All reactions were run at 125°C.
  • FIG. 6 illustrates the most relevant reaction mechanisms for the Bronsted acid- catalyzed dehydration of glucose.
  • Relevant species are numbered 1-glucose; 2-fructose and 3-HMF.
  • Pathway A is the top horizontal path from 1 to 2 to 3; pathway B is the path from 1 to 3 without going through 2; and pathway C is the bottom horizontal path from 1 to 2 to 3.
  • FIG. 7a illustrates glucose conversion and FIG. 7b HMF yield vs. a time profile for glucose dehydration in the ketone solvents of MIBK, 2-pentanone, 2-butanone and 4-heptanone.
  • FIG. 7c illustrates glucose conversion and FIG. 7d HMF yield in 1- butanol and 2-pentanol and gamma valerolactone. All reactions were run at 125°C and with 4% v/v of the aqueous phase.
  • FIGS. 8a through 8f illustrate L)V chromatograms of liquid chromatography analysis of post reaction mixtures in MIBK (FIG. 8a), 2-pentanone (FIG. 8b), 2- butanone (FIG. 8c), 4-heptanone (FIG. 8d), 2-pentanol (FIG. 8e) and 1-butanol (FIG. 8f).
  • the samples were collected after 2 hrs of reaction at 125 °C, 4% v/v aqueous loading.
  • the present invention includes selective deoxygenation of glucose to 5- hydroxymethylfurfural (HMF), for making products such as solvents, polymers, resins, detergents, lubricants, and fuel additives. It was discovered by the inventors that direct Bronsted acid-catalyzed dehydration of glucose to HMF obviates the need for Lewis acid catalysts completely and enables its coupling with upstream processing. The direct use of Bronsted acids was also observed to solve the previously reported problems of low glucose conversion and poor HMF yields.
  • HMF 5- hydroxymethylfurfural
  • the direct Bronsted acid-catalyzed dehydration of glucose to HMF achieves high HMF yields at low reaction temperatures, especially when using ketone-based organic rich solvents in the absence of any Lewis acid catalysts and without the need for multiple phase reaction conditions.
  • This process therefore has potential applications in biorefinery processes for making high value renewable chemicals and fuels for diverse industries and applications.
  • Direct Bronsted acid-catalyzed glucose dehydration in the aqueous phase is known to be a slow and unselective reaction resulting in marginal conversions and poor HMF selectivity.
  • the present invention demonstrates that a Bronsted acid- catalyzed process for producing HMF in high yield at low reaction temperatures can be achieved by employing a single phase, such as an organic rich solvent doped with water containing glucose and a salt. See FIG. 1. It was observed that ketone solvents are particularly effective in the selective dehydration of glucose. In a preferred embodiment, methyl isobutyl ketone (MIBK) is the ketone solvent and the result is high yields of HMF.
  • MIBK methyl isobutyl ketone
  • the present invention bypasses the need for any Lewis acid catalysts, and the use of a single phase in a preferred embodiment avoids the potential problems associated with a two phase system that requires complex design and transport effects, and costly separation steps in downstream processes.
  • the present invention does not follow the conventional tradition of co-solvents in an aqueous phase. Instead, the invention makes use of non-polar, organic-rich solvent systems doped with water for the thermodynamically unfavorable glucose dehydration to HMF in high yields achieved without requiring a Lewis acid.
  • Techniques such as 13 C-NMR spectroscopy, kinetic isotope effect experiments, and molecular dynamics (MD) simulations reveal that the glucose undergoes dehydration through a water-enabled acyclic mechanism.
  • ketone solvents promote enhanced interactions between the ring oxygen and the catalyst, enabling protonation at the 0-5 position, followed by ring-opening and dehydration.
  • solvents modulate the interactions between the acid catalysts and the different hydroxyl groups in the glucose molecule to overcome the well known low reactivity and selectivity issues associated with glucose.
  • the organic solvent employed in the described method comprises or consists essentially of, or consists of at least one Ci to Ce straight chain, branched, or cyclic alkyl alcohol selected from methanol, ethanol, 1-propanol, 1- butanol, 1-pentanol, 1-hexanol, isopropanol, isobutanol, sec-butanol, tert-butanol, isoamyl alcohol, 2-methyl-l-butanol, neopentyl alcohol, 2-pentanol, 3-methyl-2- butanol, 3-pentanol, tert-amyl alcohol, 2-hexanol, 3-hexanol, 2-methyl-l-pentanol, 3- methyl-l-pentanol, 4-methyl-l-pentanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 2-methyl-3-pentan
  • the organic solvent employed in the described method comprises or consists essentially of, or consists of at least one C2 to C8 ketone, such as, but not limited to, methyl isobutyl ketone (MIBK), methyl ethyl ketone (2-butanone), 2-pentanone, 4-heptanone, cyclohexanone, acetone (2-propanone) and diisobutyl ketone.
  • MIBK methyl isobutyl ketone
  • 2-butanone 2-pentanone
  • 4-heptanone 4-heptanone
  • cyclohexanone acetone (2-propanone)
  • diisobutyl ketone diisobutyl ketone
  • the organic solvent employed in the described method comprises or consists essentially of, or consists of at least one lactone selected from y-butyrolactone, methylated, ethylated, and propylated forms of y-butyrolactone and p-propiolactones.
  • the Bronsted acid catalyst employed in the described method comprises, consists essentially of, or consists of acetic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid phosphoric acid, or any combination thereof, preferably hydrochloric acid.
  • the salt optionally present in the described method comprises, consists essentially of, or consists of at least one alkali halide or alkaline-earth halide (such as lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide, calcium chloride, magnesium chloride, calcium bromide, magnesium bromide, calcium iodide and magnesium iodide).
  • alkali halide or alkaline-earth halide such as lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide, calcium chloride, magnesium chloride, calcium bromide, magnesium bromide, calcium iodide and magnesium iodide.
  • the salt comprises, consists essentially of, or consists of inorganic or organic ammonium salts, sulfate salts, phosphate salts (Grundl et aL, Journal of Molecular Liquids 236, 368-375 (2017)).
  • the salt comprises, consists essentially of, or consists of organic salts, such as, but not limited to, acetate, benzoate, benzenesulfonate, succinate, fumarate, tartrate, lactate, maleate, tosylate and mesylate salts.
  • the aqueous phase of the described method has a concentration of the salt in a range of about 0.05 M to about 0.25 M, such as about 0.05 to about 0.15 M, such as about 0.05 to about 0.15 M, such as about 0.05 to about 0.10 M, such as about 0.1 M to 0.2 M.
  • the reaction temperature of the described method ranges from about 105 °C to about 145 °C, such as about 105 °C to about 135 °C, such as about 105 °C to about 125 °C, such as about 105 °C to about 115 °C, such as about 110 °C to about 135 °C, such as about 110 °C to about 125 °C, such as about 110 °C to about 115 °C, such as about 120 °C to about 145 °C, such as about 120 °C to about 135 °C.
  • the starting mixture of the described method comprises from about 2% (v/v) to about 10% (v/v), such as about 2% (v/v) to about 8% (v/v), such as about 2% (v/v) to about 5% (v/v), such as about 5% (v/v) to about 10% (v/v), of the aqueous phase.
  • the reaction time of the described method is up to 300 minutes, such as up to 200 minutes, such as up to 120 minutes, such as from about 15 minutes to about 300 minutes, such as about 30 minutes to about 300 minutes, such as about 60 minutes to about 300 minutes, such as about 90 minutes to about 300 minutes, such as about 120 minutes to about 300 minutes, such as about 180 minutes to about 300 minutes, such as about 60 minutes to about 200 minutes, such as about 90 minutes to about 200 minutes, such as about 120 minutes to about 200 minutes.
  • the aqueous phase of the described method has a concentration of the glucose of about 0.05 M to about 0.3 M, such as about 0.05 M to about 0.2 M, such as about 0.05 M to about 0.1 M, such as about 0.1 M to about 0.3 M, such as about 0.1 M to about 0.2 M.
  • the aqueous phase of the described method has a concentration of the Bronsted acid catalyst of about 0.25 M to about 1.0 M, such as about 0.25 M to about 0.8 M, such as about 0.25 M to about 0.6 M, such as about 0.25 M to about 0.4 M, such as about 0.35 M to about 1.0 M, such as about 0.35 M to about 0.8 M, such as about 0.35 M to about 0.6 M, such as about 0.5 M to about 1.0 M.
  • the glucose is obtained by contacting cellulose in a two-step process under acidic conditions, where the first step (pre-treatment) decrystallizes cellulose to an amorphous form, while the second step (post-hydrolysis) converts the amorphous cellulose to glucose.
  • the 5- hydroxymethylfurfural (HMF) is obtained in a yield of at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 99%, such as about 50% to about 99%, such as about 65% to about 99%, such as about 75% to about 99%, such as about 50% to about 85%, such as about 55% to about 85%, such as about 60% to about 85%, such as about 65% to about 80%, based on the amount of glucose starting material.
  • the described method takes place in a single phase system containing an organic phase with a small portion of water that is soluble in the organic phase.
  • the described method takes place in a biphasic system containing water in large concentration and an organic solvent in large concentration where a portion of the water will go into the organic phase.
  • the reaction as described herein occurs to form HMF.
  • this biphasic approach there may be some loss of selectivity that results in the formation of undesired by-products in the water phase.
  • the organic solvent is added to an aqueous phase containing the glucose, Bronsted acid and optional salt reactants.
  • the glucose, Bronsted acid, and optional salt reactants are prepared separately and added to the organic solvent.
  • LC-MS measurements were carried out in a Q Exactive Orbitrap interfaced with a Dionex ultimate 3000 UHPLC system (Thermo Scientific). The sample was loaded on an ACQUITY UPLC BEH C18 1.7 pm reverse-phase column (30 mm x 2.1mm). Elution was carried out with a 6-min gradient going from 0% B to 90% B at a flow rate of 0.5 mL/min. Solvent A was water containing 0.1% formic acid, and solvent B was acetonitrile containing 0.1% formic acid. MS data were acquired in full scan mode with a mass range of 100 to 1000 m/z.
  • Hybrid QM/MM MD simulations for a system containing a hydrated proton (specific acid in water) were performed in AMBER 18.
  • the QM region consisted of the hydrated proton (with 6 solvation water molecules) and one glucose molecule modeled at the semi-empirical PM6 theory level.
  • a Cl- anion was placed in the MM region.
  • the MM region consisted of 22 water and 817 organic solvent molecules (MIBK or 2-pentanol).
  • MIBK or 2-pentanol organic solvent molecules
  • the TIP3P model was used for water and the OPLS-AA force field for MIBK and 2-pentanol.
  • the simulations were performed in a cubic simulation box of length 55.4 A; periodic boundary conditions were enforced in all three dimensions.
  • the simulation box was built using Packmol, and the MD trajectories were analyzed in VMD (Visual MD). All simulations were carried out in the NVT ensemble at 398 K with a Langevin thermostat (collision frequency of 1 ps -1 ).
  • the simulations were run for an equilibration period of 500 ps and an additional observation period of 2 ns.
  • FIG. 2a illustrates the solvent system containing 96 (v/v %) MIBK and 4 (v/v %) aqueous phase (pH 0.7 Buffer: 0.41 M HCI, 0.12 M KCI, and 0.2 M glucose).
  • the MIBK/aqueous mixture becomes miscible.
  • unfavorable organic solvent-water interactions induce molecular scale separation as the water organizes tightly around the hydrophilic substrate creating hydrophilic and hydrophobic domains (Mellmer, M. A et al., Nat. CataL 1, 199-207 (2016); Zhang, J. et aL, AppL CataL B Environ.
  • the aqueous system a solution of 0.41 M HCI, 0.12 M KCI, and 0.2 M glucose is referred to as "the aqueous system," while “the MIBK system” is the miscible mixture of MIBK doped with 4 (v/v%) of the aqueous system unless otherwise stated.
  • FIG. 2b shows the reaction profiles for glucose dehydration in the MIBK and aqueous systems.
  • Bronsted acid-catalyzed conversion of glucose can follow several proton-initiated pathways leading to condensation, mutarotation, isomerization, and dehydration (Yang, G. et aL, J CataL 295, 122-132 (2012); Lin, X. et aL, Phys. Chem. Chem. Phys. 15, 2967-2982 (2013); Qian, X., Top. CataL 55, 218-226 (2012); Qian, X. et aL, Carbohydr. Res. 388, 50-60 (2014)).
  • DFT Density Functional Theory
  • MD molecular dynamics
  • Dimerization is initiated by the protonation of Cl-OH, which exhibits the lowest free energy of protonation.
  • the protonated substrate undergoes dehydration forming a carbocation stabilized by the neighboring ring oxygen.
  • An ether bond is formed between the carbocation and one of the multiple hydroxyl groups of a second glucose molecule, resulting in reversion products and humins precursors.
  • FIG. 4 shows the formation of 1,4 cellobiose as an example.
  • the initial dimerization appears to be the most favorable pathway.
  • protonation of Cl-OH in MIBK does not predominantly lead to humins but rather to the reversible formation of dimers.
  • the equilibrium between disaccharides and glucose is affected by the irreversible consumption of glucose to HMF.
  • Anomer distribution and mutarotation are critical aspects of hexose isomerization and dehydration (Kimura, H. et aL, J Phys. Chem. A 117, 2102-2113 (2013); Shi, K. et al., J Mai. Liq. 271, 926-932 (2016); Tucker, M. H. et al., ACS Sustain. Chem. Eng. 1, 554-560 (2013); Svenningsen, G. S. et aL, ACS CataL 8, 5591- 5600 (2016); Swift, T. D. et aL, ACS CataL 4, 259-267 (2014)).
  • FIGS. 5a to 5c shows that adding acetone does not affect the HMF yield at soluble water loadings but prevents selectivity loss in aqueous to organic ratios higher than the water solubility, corroborating with the formation of a biphasic system and unselective chemistry happening in the aqueous phase.
  • FIG. 6 depicts the most predominant reaction mechanisms for Bronsted acid dehydration of glucose to HMF, including a direct dehydration pathway (B) and cyclic (A) and acyclic (C) mechanisms with the intermediate formation of fructose.
  • B direct dehydration pathway
  • A cyclic
  • C acyclic
  • results described herein demonstrate the differences in reactivity and selectivity in alcohols and ketones and the more generally, the potential of solvent- guided protonation in hexose dehydration. Creating an adequate solvent environment enables the selective protonation of the glucose ring oxygen which enhances HMF formation at the expense of protonating other sites which lead to undesired byproducts. Further, the difference in reactivity between 2-pentanol and MIBK and the strength of interactions between the catalyst and the ring 05 supports the acyclic mechanism for glucose dehydration.
  • direct Bronsted acid-catalyzed glucose dehydration in nonpolar, organic-rich systems as opposed to in aqueous media provided HMF in high yields at low reaction temperatures and without the necessity for a Lewis acid catalyst.
  • ketones were observed to promote the selective dehydration of glucose, likely by enhancing catalyst-substrate interactions at the ring oxygen promoting dehydration, alcohols likely enhance the protonation of the secondary hydroxyl groups of the glucose molecule, leading to reversion products and humins.
  • Carefully selected solvents have the potential of impacting the protonation of the target glucose oxygen, thus maximizing the desired conversion to HMF and minimizing protonation of hydroxyl groups leading to undesirable by-products.
  • the selective Bronsted acid-catalyzed glucose dehydration may enable coupling with the upstream acid-catalyzed hydrolysis of cellulose, thus avoiding costly intermediate separation steps.

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Abstract

A method is described for preparing 5-hydroxymethylfurfural (5-HMF) by forming or providing a starting mixture of an organic solvent and an aqueous phase, the aqueous phase comprising water, glucose, and a Bronsted acid catalyst, and subjecting the starting mixture to reaction conditions sufficient to convert the glucose directly to 5-HMF by acid-catalyzed dehydration. Also described is a method for preparing 5-HMF comprising contacting an aqueous phase comprising water, glucose, and a Bronsted acid catalyst with an organic solvent under reaction conditions sufficient to produce the 5-HMF directly from the glucose by acid-catalyzed dehydration.

Description

DIRECT BR0NSTED ACID-CATALYZED DEHYDRATION OF GLUCOSE TO 5- HYDROXYM ETHYLFURFURAL
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to United States Provisional Application No. 63/447,919, filed February 24, 2023, the contents of which is incorporated herein by reference in its entirety for all purposes. STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH
This invention was made with government support under contract DE- EE0007888-7.6 awarded by the U.S. Department of Energy. The government has certain rights in the invention. BACKGROUND OF THE INVENTION
Glucose is the most abundant monosaccharide in biomass feedstocks. Its efficient valorization is essential for an economically viable transition from the currently prevalent fossil fuels-based to a sustainable chemical industry (Behrens, M. et aL, Catalysis for the Conversion of Biomass and Its Derivatives (e-published 2013); Chheda, J. N. et aL, Angew. Chemie Int. Ed 46, 7164-7183 (2007); Bender, T. A. et aL, Nat. Rev. Chem. 2, 35-46 (2018); Thoma, C. et aL, ChemSusChem 13, 3544-3564 (2020); Van Putten, R.-J. J. et aL, Chem. Rev. 113, 1499-1597 (2013); Zou, X. et al., Biofuels, Bioprod Biorefining 13, 153-173 (2019); Wang, T. et aL, Green Chem. 16, 548-572 (2014); Zhu, L. et al., ChemSusChem 13, 4812-4832 (2020)). Efforts have been reported regarding the conversion of glucose into 5-hydroxymethylfurfural (HMF), which is widely recognized as a key intermediate in the production of biomass-derived fuels, polymers, and other products (Delbecq, F. et aL, Front. Chem. 6, 146 (2018)).
Chemo-catalytic deoxygenation is traditionally carried out through dehydration using Bronsted acids. However, marginal conversions and poor selectivity in aqueous systems have hindered the direct transformation of glucose (Van Putten, R.-J. J. et aL, Chem. Rev. 113, 1499-1597 (2013); Zou, X. et aL, Biofuels, Bioprod Biorefining 13, 153-173 (2019); Zhu, L. et aL, ChemSusChem 13, 4812- 4832 (2020); Delbecq, F. et aL, Front. Chem. 6, 146 (2018); Van Putten, R. J. et al., ChemSusChem 6, 1681-1687 (2013); Yang, G. et al., J CataL 295, 122-132 (2012); Garrett, E. R. et aL, J Pharm. Sci. 58, 813-820 (1969); Ramesh, P. et al., React. Chem. Eng. 4, 273-277 (2019)). Computational studies have attributed the low reactivity to the high stability of the glucose pyranose ring structure and the low selectivity to the reactive, secondary hydroxyl groups with high protonation energies, leading to low-value byproducts via parallel pathways (Van Putten, R.-J. J. et aL, Chem. Rev. 113, 1499-1597 (2013); Yang, G. et aL, J CataL 295, 122-132 (2012); Lin, X. et aL, Phys. Chem. Chem. Phys. 15, 2967-2982 (2013); Qian, X. et aL, Top. CataL 55, 218-226 (2012); Assary, R. S. et al., Phys. Chem. Chem. Phys. 14, 16603-16611 (2012); Kuster, B. F. M. et aL, Starch-Starke 42, 314-321 (1990)).
Efforts to overcome the low reactivity have focused on Lewis acid-catalyzed isomerization of glucose to its more reactive anomer, fructose (Zhu, L. et al., ChemSusChem 13, 4812-4832 (2020)). Nevertheless, this strategy requires higher temperatures, long processing times, and homogeneous Lewis acid catalysts, which can be toxic and difficult to separate. Alternatively, heterogeneous Lewis acid catalysts can be used but pose other challenges, including stability/regeneration, clogging, mass transfer limitations, and poisoning of their active sites from impurities in raw biomass. A two-step synthesis of HMF using both Lewis acids and Bronsted acids requires higher cost, high temperatures, long processing times, and catalyst separation.
The use of biphasic systems has been observed to improve the yield of HMF but undesirably adds cost and increased energy use. Early studies explored polar cosolvents and biphasic systems for the dehydration of furanoses, fructose and xylose, resulting in remarkable improvements in the selectivity to HMF and furfural, respectively (Saha, B. et aL, Green Chem. 16, 24-38 (2014); Roman-Leshkov, Y. et aL, Science (80) 312, 1933 (2006); Roman-Leshkov, Y. et aL, Top. CataL 52, 297-303 (2009); Esteban, J. et al., Green Chem. 22, 2097-2128 (2020); Wrigstedt, P. et aL, RSC Adv. 6, 18973-18979 (2016); Roman-Leshkov, Y. et aL, Nature 44, 982-986 (2007)). Previous investigations in biphasic microfluidics, exhibiting high mass transfer across phases, expose significant partitioning of the aqueous phase into the non-polar organic extractive phase at reaction temperatures. The aqueous phase in the organic phase creates nanoemulsions, rich in fructose solvated by water molecules and protons, in large organic solvent domains deprived of aqueous phase constituents. Fructose dehydration in this organic-rich media was observed to be rapid and selective towards HMF. Nevertheless, similar advancements for the less reactive pyranoses, such as glucose, have been lacking (Vasudevan, V. et aL, RSC Adv. 5, 20756-20763 (2015); Liu, Y. et aL, Pure AppL Chem. 93, 463-478 (2021)).
SUMMARY OF THE INVENTION
In a first exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural, comprising the steps of:
(a) forming or providing a starting mixture, the starting mixture comprising : i. an organic solvent; and il. an aqueous phase, the aqueous phase comprising water, glucose, and a Bronsted acid catalyst; and (b) subjecting the starting mixture (a) to reaction conditions sufficient to convert the glucose directly to 5-hydroxymethylfurfural.
In a further exemplary embodiment, the starting mixture is a single phase.
In a further exemplary embodiment, the starting mixture is a biphase.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural, comprising combining water, glucose, a Bronsted acid catalyst and an organic solvent under reaction conditions sufficient to produce the 5-hydroxyfurfural directly from the glucose.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural, comprising contacting an aqueous phase comprising, consisting essentially of, or consisting of water, glucose, and a Brpnsted acid catalyst with an organic solvent under reaction conditions sufficient to produce the 5-hydroxyfurfural directly from the glucose.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the organic solvent comprises one or more of alcohols, ketones, lactones, or any combination thereof.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the alcohol comprises one or more Cl to C6 straight chain, branched, or cyclic alkyl alcohols.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the alcohol comprises, consists essentially of, or consists of 1-butanol, 2-pentanol, or any combination thereof.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the ketone comprises, consists essentially of, or consists of methyl isobutyl ketone, 2-butanone, 2-pentanone, 4-heptanone, 2-propanone, or any combination thereof.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the organic solvent comprises, consists essentially of, or consists of methyl isobutyl ketone.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the Bronsted acid catalyst comprises, consists essentially of, or consists of hydrochloric acid, sulfuric acid, phosphoric acid, or any combination thereof, preferably hydrochloric acid.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase further comprises a salt, such as an organic salt or an inorganic salt, preferably an inorganic salt.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the salt comprises, consists essentially of, or consists of sodium chloride and/or potassium chloride.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase has a concentration of the salt in a range of about 0.05 M to about 0.25 M.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein a temperature the reaction conditions in (b) include a temperature in a range of about 105 °C to about 145 °C.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the starting mixture comprises about 2% (v/v) to about 10% (v/v), preferably about 2% (v/v) to about 5% (v/v), of the aqueous phase.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein a reaction time under the reaction conditions in (b) is in a range of up to about 300 minutes, preferably about 60 minutes to about 180 minutes.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase has a concentration of the glucose in a range of about 0.05 M to about 0.3 M.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the aqueous phase has a concentration of the Bronsted acid catalyst in a range of about 0.25 M to about 1.0 M.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the glucose is obtained by contacting cellulose with an acidic aqueous solution.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the cellulose that serves as the source of the glucose is obtained from a non-edible lignocellulosic biomass.
In a further exemplary embodiment, the invention relates to a method of preparing 5-hydroxymethylfurfural as described, wherein the 5-hydroxymethylfurfural is obtained in at least a 50% yield, preferably in at least a 75% yield based on the amount of glucose starting material.
BRIEF DESCRIPTION OF THE DRAWINGS The figures described herein are merely illustrative of exemplary embodiments of the present invention and are not intended to narrow the breadth of the invention as otherwise described.
FIG. 1 illustrates how in the present invention, glucose can be directly converted into HMF compared to conventional methods that proceed through a fructose intermediate.
FIG. 2a illustrates a schematic representation of a methyl isobutyl ketone (MIBK)-rich system with miscible amounts of the reactive aqueous phase at reaction temperature. FIG. 2b shows glucose conversion and HMF yield in a single MIBK phase reaction with soluble amounts of the aqueous solution (upper squares and circles) and the aqueous phase reaction (lower squares and circles). FIG. 2c shows a HMF selectivity profile (circles) and sugar dimer yield (squares) in the MIBK system. All reactions were run at 125 °C.
FIG. 3a illustrates HPLC chromatograms of reaction mixtures after 270 minutes at 125 °C using a RI-410 detector. FIG. 3b illustrates HPLC chromatograms of reaction mixtures after 270 minutes at 125 °C using a UV detector at 254 nm. The most relevant by-product species observed include glucose (G), sugar dimers (disaccharides) (D), formic acid (FA), levulinic acid (LA), HMF and an unidentified byproduct (BP).
FIG. 4 illustrates a reaction mechanism for the proton-initiated dimerization of glucose to 1,4 cellobiose.
FIG. 5a, FIG. 5b and FIG. 5c illustrate the acetone effect on the yield of HMF in MIBK with increasing aqueous to organic ratios (organic: aqueous) of 1 :0.04 (FIG. 5a); 1 :0.06 (FIG. 5b); and 1:0.08 (FIG. 5c). All reactions were run at 125°C.
FIG. 6 illustrates the most relevant reaction mechanisms for the Bronsted acid- catalyzed dehydration of glucose. Relevant species are numbered 1-glucose; 2-fructose and 3-HMF. Pathway A is the top horizontal path from 1 to 2 to 3; pathway B is the path from 1 to 3 without going through 2; and pathway C is the bottom horizontal path from 1 to 2 to 3.
FIG. 7a illustrates glucose conversion and FIG. 7b HMF yield vs. a time profile for glucose dehydration in the ketone solvents of MIBK, 2-pentanone, 2-butanone and 4-heptanone. FIG. 7c illustrates glucose conversion and FIG. 7d HMF yield in 1- butanol and 2-pentanol and gamma valerolactone. All reactions were run at 125°C and with 4% v/v of the aqueous phase.
FIGS. 8a through 8f illustrate L)V chromatograms of liquid chromatography analysis of post reaction mixtures in MIBK (FIG. 8a), 2-pentanone (FIG. 8b), 2- butanone (FIG. 8c), 4-heptanone (FIG. 8d), 2-pentanol (FIG. 8e) and 1-butanol (FIG. 8f). The samples were collected after 2 hrs of reaction at 125 °C, 4% v/v aqueous loading.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes selective deoxygenation of glucose to 5- hydroxymethylfurfural (HMF), for making products such as solvents, polymers, resins, detergents, lubricants, and fuel additives. It was discovered by the inventors that direct Bronsted acid-catalyzed dehydration of glucose to HMF obviates the need for Lewis acid catalysts completely and enables its coupling with upstream processing. The direct use of Bronsted acids was also observed to solve the previously reported problems of low glucose conversion and poor HMF yields. As described herein, the direct Bronsted acid-catalyzed dehydration of glucose to HMF achieves high HMF yields at low reaction temperatures, especially when using ketone-based organic rich solvents in the absence of any Lewis acid catalysts and without the need for multiple phase reaction conditions. This process therefore has potential applications in biorefinery processes for making high value renewable chemicals and fuels for diverse industries and applications.
Direct Bronsted acid-catalyzed glucose dehydration in the aqueous phase is known to be a slow and unselective reaction resulting in marginal conversions and poor HMF selectivity. The present invention demonstrates that a Bronsted acid- catalyzed process for producing HMF in high yield at low reaction temperatures can be achieved by employing a single phase, such as an organic rich solvent doped with water containing glucose and a salt. See FIG. 1. It was observed that ketone solvents are particularly effective in the selective dehydration of glucose. In a preferred embodiment, methyl isobutyl ketone (MIBK) is the ketone solvent and the result is high yields of HMF. The present invention bypasses the need for any Lewis acid catalysts, and the use of a single phase in a preferred embodiment avoids the potential problems associated with a two phase system that requires complex design and transport effects, and costly separation steps in downstream processes.
The present invention does not follow the conventional tradition of co-solvents in an aqueous phase. Instead, the invention makes use of non-polar, organic-rich solvent systems doped with water for the thermodynamically unfavorable glucose dehydration to HMF in high yields achieved without requiring a Lewis acid. Techniques such as 13C-NMR spectroscopy, kinetic isotope effect experiments, and molecular dynamics (MD) simulations reveal that the glucose undergoes dehydration through a water-enabled acyclic mechanism. Without being bound by theory, it appears that the evidence suggests that ketone solvents promote enhanced interactions between the ring oxygen and the catalyst, enabling protonation at the 0-5 position, followed by ring-opening and dehydration. Significantly, solvents modulate the interactions between the acid catalysts and the different hydroxyl groups in the glucose molecule to overcome the well known low reactivity and selectivity issues associated with glucose.
In an exemplary embodiment, the organic solvent employed in the described method comprises or consists essentially of, or consists of at least one Ci to Ce straight chain, branched, or cyclic alkyl alcohol selected from methanol, ethanol, 1-propanol, 1- butanol, 1-pentanol, 1-hexanol, isopropanol, isobutanol, sec-butanol, tert-butanol, isoamyl alcohol, 2-methyl-l-butanol, neopentyl alcohol, 2-pentanol, 3-methyl-2- butanol, 3-pentanol, tert-amyl alcohol, 2-hexanol, 3-hexanol, 2-methyl-l-pentanol, 3- methyl-l-pentanol, 4-methyl-l-pentanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 2-methyl-3-pentanol, 3-methyl-3-pentanol, 2,2-dimethyl-l- butanol, 2,3-dimethyl-l-butanol and 3,3-dimethyl-l-butanol.
In an exemplary embodiment, the organic solvent employed in the described method comprises or consists essentially of, or consists of at least one C2 to C8 ketone, such as, but not limited to, methyl isobutyl ketone (MIBK), methyl ethyl ketone (2-butanone), 2-pentanone, 4-heptanone, cyclohexanone, acetone (2-propanone) and diisobutyl ketone.
In an exemplary embodiment, the organic solvent employed in the described method comprises or consists essentially of, or consists of at least one lactone selected from y-butyrolactone, methylated, ethylated, and propylated forms of y-butyrolactone and p-propiolactones.
In an exemplary embodiment, the Bronsted acid catalyst employed in the described method comprises, consists essentially of, or consists of acetic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid phosphoric acid, or any combination thereof, preferably hydrochloric acid.
In an exemplary embodiment, the salt optionally present in the described method comprises, consists essentially of, or consists of at least one alkali halide or alkaline-earth halide (such as lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide, calcium chloride, magnesium chloride, calcium bromide, magnesium bromide, calcium iodide and magnesium iodide). In another exemplary embodiment, the salt comprises, consists essentially of, or consists of inorganic or organic ammonium salts, sulfate salts, phosphate salts (Grundl et aL, Journal of Molecular Liquids 236, 368-375 (2017)). In another exemplary embodiment, the salt comprises, consists essentially of, or consists of organic salts, such as, but not limited to, acetate, benzoate, benzenesulfonate, succinate, fumarate, tartrate, lactate, maleate, tosylate and mesylate salts. In an exemplary embodiment, the aqueous phase of the described method has a concentration of the salt in a range of about 0.05 M to about 0.25 M, such as about 0.05 to about 0.15 M, such as about 0.05 to about 0.15 M, such as about 0.05 to about 0.10 M, such as about 0.1 M to 0.2 M.
In an exemplary embodiment, the reaction temperature of the described method ranges from about 105 °C to about 145 °C, such as about 105 °C to about 135 °C, such as about 105 °C to about 125 °C, such as about 105 °C to about 115 °C, such as about 110 °C to about 135 °C, such as about 110 °C to about 125 °C, such as about 110 °C to about 115 °C, such as about 120 °C to about 145 °C, such as about 120 °C to about 135 °C.
In an exemplary embodiment, the starting mixture of the described method comprises from about 2% (v/v) to about 10% (v/v), such as about 2% (v/v) to about 8% (v/v), such as about 2% (v/v) to about 5% (v/v), such as about 5% (v/v) to about 10% (v/v), of the aqueous phase.
In an exemplary embodiment, the reaction time of the described method is up to 300 minutes, such as up to 200 minutes, such as up to 120 minutes, such as from about 15 minutes to about 300 minutes, such as about 30 minutes to about 300 minutes, such as about 60 minutes to about 300 minutes, such as about 90 minutes to about 300 minutes, such as about 120 minutes to about 300 minutes, such as about 180 minutes to about 300 minutes, such as about 60 minutes to about 200 minutes, such as about 90 minutes to about 200 minutes, such as about 120 minutes to about 200 minutes.
In an exemplary embodiment, the aqueous phase of the described method has a concentration of the glucose of about 0.05 M to about 0.3 M, such as about 0.05 M to about 0.2 M, such as about 0.05 M to about 0.1 M, such as about 0.1 M to about 0.3 M, such as about 0.1 M to about 0.2 M.
In an exemplary embodiment, the aqueous phase of the described method has a concentration of the Bronsted acid catalyst of about 0.25 M to about 1.0 M, such as about 0.25 M to about 0.8 M, such as about 0.25 M to about 0.6 M, such as about 0.25 M to about 0.4 M, such as about 0.35 M to about 1.0 M, such as about 0.35 M to about 0.8 M, such as about 0.35 M to about 0.6 M, such as about 0.5 M to about 1.0 M.
In an exemplary embodiment of the described method, the glucose is obtained by contacting cellulose in a two-step process under acidic conditions, where the first step (pre-treatment) decrystallizes cellulose to an amorphous form, while the second step (post-hydrolysis) converts the amorphous cellulose to glucose. In an exemplary embodiment of the described method, the 5- hydroxymethylfurfural (HMF) is obtained in a yield of at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 99%, such as about 50% to about 99%, such as about 65% to about 99%, such as about 75% to about 99%, such as about 50% to about 85%, such as about 55% to about 85%, such as about 60% to about 85%, such as about 65% to about 80%, based on the amount of glucose starting material.
In a preferred embodiment, the described method takes place in a single phase system containing an organic phase with a small portion of water that is soluble in the organic phase.
In an exemplary embodiment, the described method takes place in a biphasic system containing water in large concentration and an organic solvent in large concentration where a portion of the water will go into the organic phase. In the resulting organic phase containing a miscible portion of water, the reaction as described herein occurs to form HMF. When using this biphasic approach, there may be some loss of selectivity that results in the formation of undesired by-products in the water phase.
In an exemplary embodiment of the starting mixture, the organic solvent is added to an aqueous phase containing the glucose, Bronsted acid and optional salt reactants.
In another exemplary embodiment, the glucose, Bronsted acid, and optional salt reactants are prepared separately and added to the organic solvent.
In another exemplary embodiment, there is no limitation on the order of how the glucose, Bronsted acid, optional salt reactants and the organic solvent are combined.
Experimental Methods
All reactions were carried out in batch in 8 ml glass vials (ChemGlass) sealed with aluminum and silicon septa caps (ChemGlass). The sealed vials were heated in a preheated aluminum block consisting of wells filled with silicon oil and stirred at 900 rpm. Immediately after the target reaction time, the vials were quenched in an ice bath.
Sampling and quantifying reactants and products in reaction mixtures containing more than 90% organic solvent required after-reaction extraction of water- soluble compounds. For these systems, 2 ml of reagent grade water (Fischer Scientific) was added to the reaction mixture after quenching. The biphasic mixture was then vortexed and allowed to phase separate. The two phases were then sampled separately. Quantification was carried out via High-Performance Liquid Chromatography (HPLC) on a Waters Alliance Instruments e2692 HPLC equipped with photodiode array (Waters 2998) and reflective index (Waters 2414) detectors. Separation was done on a Bio-Rad HPX-87H column maintained at 55 °C. The mobile phase was 0.005 M H2SO4 flowing at 0.6 ml/min.
The conversion and the yield were calculated as follows: glucose — glucose
Conversion (°/o) = x 100%
C gt=lu0cose
Figure imgf000011_0001
All 13C NMR spectra were acquired on an Avance III 400 MHz NMR spectrometer (Bruker) equipped with a BBFO probe (Bruker). Samples for in-situ measurements consisted of 50 pL of 0.5M D-Glucose-13C-(l-6) (Cambridge Isotope Laboratories) in water and 500 pL of MIBK. 200 pL of acetone-ds was added to homogenize the mixture and as a solvent lock for spectra acquisition. To maximize the signal in such a dilute solution, 1036 scans were acquired. The samples were prepared in high-temperature, high-pressure NMR tubes from NORELL (S-5-400-MW-IPV-8) and allowed to reach the target temperature before acquisition. The NMR data were processed using the Mestrelab Research Software (mNOVA).
LC-MS measurements were carried out in a Q Exactive Orbitrap interfaced with a Dionex ultimate 3000 UHPLC system (Thermo Scientific). The sample was loaded on an ACQUITY UPLC BEH C18 1.7 pm reverse-phase column (30 mm x 2.1mm). Elution was carried out with a 6-min gradient going from 0% B to 90% B at a flow rate of 0.5 mL/min. Solvent A was water containing 0.1% formic acid, and solvent B was acetonitrile containing 0.1% formic acid. MS data were acquired in full scan mode with a mass range of 100 to 1000 m/z.
Hybrid QM/MM MD simulations for a system containing a hydrated proton (specific acid in water) were performed in AMBER 18. The QM region consisted of the hydrated proton (with 6 solvation water molecules) and one glucose molecule modeled at the semi-empirical PM6 theory level. To maintain electroneutrality, a Cl- anion was placed in the MM region. The MM region consisted of 22 water and 817 organic solvent molecules (MIBK or 2-pentanol). For the glucose and hydronium, we used the GLYCAM- 06j-l and General Amber force field, respectively. The TIP3P model was used for water and the OPLS-AA force field for MIBK and 2-pentanol. The simulations were performed in a cubic simulation box of length 55.4 A; periodic boundary conditions were enforced in all three dimensions. The simulation box was built using Packmol, and the MD trajectories were analyzed in VMD (Visual MD). All simulations were carried out in the NVT ensemble at 398 K with a Langevin thermostat (collision frequency of 1 ps -1). We employed the minimum image convention for the short-range interactions, with a cutoff of 20 A, and the Particle Mesh Ewald method for the long-range electrostatic interactions, with a short-range cutoff of 20 A. For the interactions between the QM and MM regions, we used a cutoff radius of 10 A. The simulations were run for an equilibration period of 500 ps and an additional observation period of 2 ns.
To maintain a compact QM region in the course of the dynamics, the restraining potential
Figure imgf000012_0002
= 0,5 & (r -
Figure imgf000012_0001
- 18), where 0(r) is the Heaviside step function, was applied to all pairwise atomic interactions between the solute and the solvent in the QM region; r is in units of A and & = 1 kcal/(mol A2) proved sufficient to keep the QM region from spreading out. All reported expectation values and pair correlation functions were properly unbiased to remove the effect of the restraining potential. Results
Bronsted Acid-Catalyzed Dehydration of Glucose in MIBK: FIG. 2a illustrates the solvent system containing 96 (v/v %) MIBK and 4 (v/v %) aqueous phase (pH 0.7 Buffer: 0.41 M HCI, 0.12 M KCI, and 0.2 M glucose). At the reaction temperature, the MIBK/aqueous mixture becomes miscible. Yet, unfavorable organic solvent-water interactions induce molecular scale separation as the water organizes tightly around the hydrophilic substrate creating hydrophilic and hydrophobic domains (Mellmer, M. A et al., Nat. CataL 1, 199-207 (2018); Zhang, J. et aL, AppL CataL B Environ. 181, 874-887 (2016); Varghese, J. J. et aL, React. Chem. Eng. 4, 165-206 (2019); Walker, T. W. et aL, Energy Environ. Sci. 11, 617-628 (2018)). Hereafter, a solution of 0.41 M HCI, 0.12 M KCI, and 0.2 M glucose is referred to as "the aqueous system," while "the MIBK system" is the miscible mixture of MIBK doped with 4 (v/v%) of the aqueous system unless otherwise stated.
FIG. 2b shows the reaction profiles for glucose dehydration in the MIBK and aqueous systems. In agreement with previous reports (Van Putten, R. J. et aL, ChemSusChem 6, 1681-1687 (2013); Girisuta, B. et aL, Chem. Eng. Res. Des. 84, 339-349 (2006); Heimlich, K. R. et al., J Am. Pharm. Assoc. 49, 592-597 (2006); Mckibbins, S. W. et aL, For. Prod J 17-23 (1962); Pilath, H. M. et aL, J Agric. Food Chem. 58, 6131-6140 (2010); Tan-Soetedjo, J. N. M. et aL, Ind Eng. Chem. Res. 56, 13228-13239 (2017); T. Dallas Swift et aL, ACS Catal. 4, 259-267 (2014)), the dehydration of glucose in Bronsted acidic aqueous media is slow and unselective, also evidenced by the dark color of the reaction solution depicting humin by-products. In contrast, the dehydration of glucose in the method of the present invention is significantly faster, achieves close to complete conversion after 300 minutes, is more selective, and provides high yields of HMF in the absence of a Lewis acid catalyst. The clear color of the post-reaction mixture is evidence of the low formation of non-soluble humin byproducts.
HPLC analysis as shown in FIGS. 3a and 3b reveals the typical byproducts of HMF rehydration, levulinic and formic acid (Girisuta, B. et aL, Chem. Eng. Res. Des. 84, 339-349 (2006); Mckibbins, S. W. et al., For. Prod J 17-23 (1962)), sugar disaccharides, and a major unknown byproduct eluting after 22 minutes. The dimer yield vs. time (FIG. 2c) shows the presence of sugar dimers at short reaction times that are slowly depleted. This behavior mirrors the selectivity for HMF, indicating that the decrease in dimers is likely not due to their continuous polymerization to humins. Surprisingly, fructose was not detected.
Bronsted acid-catalyzed conversion of glucose can follow several proton-initiated pathways leading to condensation, mutarotation, isomerization, and dehydration (Yang, G. et aL, J CataL 295, 122-132 (2012); Lin, X. et aL, Phys. Chem. Chem. Phys. 15, 2967-2982 (2013); Qian, X., Top. CataL 55, 218-226 (2012); Qian, X. et aL, Carbohydr. Res. 388, 50-60 (2014)). Given the limitation of ex-situ liquid chromatography (LC) to differentiate glucose anomers, detect low concentration products, and elucidate the chemical nature of unknown components, LC-MS and in- situ 13C NMR are employed to evaluate side reactions, as elaborated below.
Density Functional Theory (DFT) and molecular dynamics (MD) studies demonstrate that condensation of monosaccharides is the most thermodynamically favored pathway for glucose conversion in Bronsted acidic media and the main reason for the low selectivity (Yang, G. et aL, J CataL 295, 122-132 (2012); Lin, X. et aL, Phys. Chem. Chem. Phys. 15, 2967-2982 (2013); Qian, X., Top. CataL 55, 218-226 (2012); Assary, R. S. et al., Phys. Chem. Chem. Phys. 14, 16603-16611 (2012); Qian, X. et aL, Carbohydr. Res. 388, 50-60 (2014)). Dimerization is initiated by the protonation of Cl-OH, which exhibits the lowest free energy of protonation. The protonated substrate undergoes dehydration forming a carbocation stabilized by the neighboring ring oxygen. An ether bond is formed between the carbocation and one of the multiple hydroxyl groups of a second glucose molecule, resulting in reversion products and humins precursors. FIG. 4 shows the formation of 1,4 cellobiose as an example. In agreement with computational studies, the initial dimerization appears to be the most favorable pathway. However, in contrast with reactions in water, protonation of Cl-OH in MIBK does not predominantly lead to humins but rather to the reversible formation of dimers. The equilibrium between disaccharides and glucose is affected by the irreversible consumption of glucose to HMF.
Anomer distribution and mutarotation are critical aspects of hexose isomerization and dehydration (Kimura, H. et aL, J Phys. Chem. A 117, 2102-2113 (2013); Shi, K. et al., J Mai. Liq. 271, 926-932 (2018); Tucker, M. H. et al., ACS Sustain. Chem. Eng. 1, 554-560 (2013); Svenningsen, G. S. et aL, ACS CataL 8, 5591- 5600 (2018); Swift, T. D. et aL, ACS CataL 4, 259-267 (2014)). Studies on glucose to fructose isomerization catalyzed by D-glucose isomerase, and metal chlorides in water and ionic liquids suggest that selective stabilization of a-glucose leads to improved selectivity to fructose (Zhao, H. et aL, Science (80). 316, 1597-1600 (2007); Ramesh, P. et aL, React. Chem. Eng. 4, 273-277 (2019); Lee, H. S. et aL, J Biotechnol. 84, 145- 153 (2000)).
Increasing the solubility of the aqueous phase in the organic phase by adding a soluble co-solvent, such as acetone or acetonitrile, allows higher aqueous loadings and productivity while maintaining selectivity. FIGS. 5a to 5c shows that adding acetone does not affect the HMF yield at soluble water loadings but prevents selectivity loss in aqueous to organic ratios higher than the water solubility, corroborating with the formation of a biphasic system and unselective chemistry happening in the aqueous phase.
Without being bound by theory, FIG. 6 depicts the most predominant reaction mechanisms for Bronsted acid dehydration of glucose to HMF, including a direct dehydration pathway (B) and cyclic (A) and acyclic (C) mechanisms with the intermediate formation of fructose. Although significant evidence supporting acyclic (Kuster, B. F. M. et aL, Starch-Starke 42, 314-321 (1990); Amarasekara, A S. et aL, Carbohydr. Res. 386, 86-91 (2014); Zunita, M. et aL, AppL Sci. 11, 1-11 (2021); Harris, D. W. et aL, Carbohydr. Res. 30, 359-365 (1973); Kunnikuruvan, S. et aL, ACS CataL 9, 7250-7263 (2019)) and cyclic (Qian, X. et aL, Top. CataL 55, 218-226 (2012); Qian, X. et aL, Carbohydr. Res. 388, 50-60 (2014); Istasse, T. et aL, RSC Adv. 10, 23720-23742 (2020); Qian, X. et aL, J Phys. Chem. B 116, 10898-10904 (2012)) pathways has been presented, it is generally agreed that the reaction mechanism is dictated by the reaction conditions and, in particular, the solvent (Wang, T. et aL, Green Chem. 16, 548-572 (2014); Liu, Y. et aL, Pure AppL Chem. 93, 463-478 (2021); Kunnikuruvan, S. et aL, ACS CataL 9, 7250-7263 (2019); Istasse, T. et al., RSC Adv. 10, 23720-23742 (2020)). Enhanced rate and selectivity associated with MIBK was observed to extend to other non-polar solvents, including alcohols and other ketones, such as 2-pentanol and 2-pentanone. It was found that the more hydrophobic the organic solvent, the stronger the microphase separation, and the more pronounced the solvent effects on reactivity. Three exemplary ketones (2-pentanone, 2-butanone, and 4-heptanone), two alcohols (2-pentanol and 1-butanol), and the biomass-derived solvent gamma valerolactone (all with 4% aqueous content) were evaluated for the direct Bronsted acid-catalyzed dehydration of glucose as shown in Figure 7.
All solvents were observed to enhance the rate of glucose conversion compared to water, achieving close to complete conversion after 300 minutes (FIGS. 7a and 7c) Unexpectedly, only ketones enhanced the formation of HMF (FIGS. 7b and 7d). The reactions in all solvents were carried out at the optimal aqueous to organic ratio for MIBK (the water solubility at the reaction temperature).
Although dehydration in alcohols was observed to be faster than in MIBK, the formation of HMF is negligible. LC-MS reveals a wider product distribution in alcohols than ketones with a prevalence of high molecular weight species associated with reversion products and humin formation (Cheng, Z. et aL, Green Chem. 20, 997-1006 (2018); Shi, N. et al., Chinese J Chem. Phys. 27, 711- 717 (2014)) as shown in FIG. 8.
The results described herein demonstrate the differences in reactivity and selectivity in alcohols and ketones and the more generally, the potential of solvent- guided protonation in hexose dehydration. Creating an adequate solvent environment enables the selective protonation of the glucose ring oxygen which enhances HMF formation at the expense of protonating other sites which lead to undesired byproducts. Further, the difference in reactivity between 2-pentanol and MIBK and the strength of interactions between the catalyst and the ring 05 supports the acyclic mechanism for glucose dehydration.
In past years, the enhancing effects of metal halides in the reactivity and selectivity of dehydration reactions have been exploited (Korner, P. et al., React. Chem. Eng. 4, 747-762 (2019); Enslow, K. R. et aL, ChemCatChem 7, 479-489 (2015); Jiang, Z. et aL, ChemSusChem 8, 1901-1907 (2015); Marcotullio, G. et aL, Green Chem. 12, 1739-1746 (2010); Mellmer, M. A et aL, Nat. Commun. 10, 1-10 (2019); Marcotullio, G. et aL, Carbohydr. Res. 346, 1291-1293 (2011); Kammoun, M. et al., Front. Chem. 7 (2019)). These promotional effects are especially prevalent in chloride salts having potassium or sodium cations and are attributed to ion stabilization of the protonated transition states and de-stabilization of the catalyst and reactants by disrupting solvation (Enslow, K. R. et aL, ChemCatChem 7, 479-489 (2015); Mellmer, M. A et aL, Nat. Commun. 10, 1-10 (2019)). As described herein, direct Bronsted acid-catalyzed glucose dehydration in nonpolar, organic-rich systems as opposed to in aqueous media provided HMF in high yields at low reaction temperatures and without the necessity for a Lewis acid catalyst. In an embodiment, ketones were observed to promote the selective dehydration of glucose, likely by enhancing catalyst-substrate interactions at the ring oxygen promoting dehydration, alcohols likely enhance the protonation of the secondary hydroxyl groups of the glucose molecule, leading to reversion products and humins. Carefully selected solvents have the potential of impacting the protonation of the target glucose oxygen, thus maximizing the desired conversion to HMF and minimizing protonation of hydroxyl groups leading to undesirable by-products. Further, the selective Bronsted acid-catalyzed glucose dehydration may enable coupling with the upstream acid-catalyzed hydrolysis of cellulose, thus avoiding costly intermediate separation steps.
Although the invention is illustrated and described herein with reference to specific embodiments, the invention is not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the invention.

Claims

What is Claimed :
1. A method of preparing 5-hydroxymethylfurfural (5-HMF), comprising:
(a) forming or providing a starting mixture, the starting mixture comprising : i. an organic solvent; and ii. an aqueous phase, the aqueous phase comprising water, glucose, and a Bronsted acid catalyst; and
(b) subjecting the starting mixture (a) to reaction conditions sufficient to directly convert the glucose to 5-HMF.
2. A method of preparing 5-hydroxymethylfurfural (5-HMF), comprising contacting an aqueous phase comprising water, glucose, and a Bronsted acid catalyst with an organic solvent under reaction conditions sufficient to produce the 5-HMF directly from the glucose.
3. The method of one of claims 1 or 2, wherein the organic solvent comprises one or more of alcohols, ketones, lactones, or any combination thereof.
4. The method of claim 3, wherein the alcohols comprise one or more Ci to Ce straight chain, branched, or cyclic alkyl alcohols.
5. The method of one of claims 3 or 4, wherein the alcohols comprise 1-butanol, 2- pentanol, or any combination thereof.
6. The method of any one of claims 3 to 5, wherein the ketones comprise methyl isobutyl ketone, 2-butanone, 2-pentanone, 4-heptanone, 2-propanone, or any combination thereof.
7. The method of any one of claims 1 to 6, wherein the organic solvent comprises methyl isobutyl ketone.
8. The method of any one of claims 1 to 7, wherein the Bronsted acid catalyst comprises hydrochloric acid, sulfuric acid, phosphoric acid, or any combination thereof.
9. The method of any of any one of claims 1 to 8, wherein the aqueous phase further comprises a salt.
10. The method of claim 9, wherein the salt comprises potassium chloride.
11. The method of claim 9 or 10, wherein aqueous phase has a concentration of the salt in a range of about 0.05 M to about 0.25 M.
12. The method of any one of claims 1 to 11, wherein a temperature under the reaction conditions is in a range of about 105 °C to about 145 °C.
13. The method of any one of claims 1 to 12, wherein the starting mixture comprises about 2% (v/v) to about 10% (v/v) of the aqueous phase.
14. The method of any one of claims 1 to 13, wherein a reaction time under the reaction conditions is in a range of up to about 300 minutes.
15. The method of any one of claims 1 to 14, wherein the aqueous phase has a concentration of the glucose in a range of about 0.05 M to about 0.3 M.
16. The method of any one of claims 1 to 15, wherein the aqueous phase has a concentration of the Bronsted acid catalyst in a range of about 0.25 M to about 1.0 M.
17. The method of any one of claims 1 to 16, wherein the glucose is obtained by contacting cellulose with an acidic aqueous solution.
18. The method of any one of claims 1 to 17, wherein the cellulose is obtained from non-edible lignocellulosic biomass.
PCT/US2024/016994 2023-02-24 2024-02-23 Direct bronsted acid-catalyzed dehydration of glucose to 5-hydroxymethylfurfural WO2024178283A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130150595A1 (en) * 2011-12-07 2013-06-13 James A. Dumesic Lewis and bronsted-lowry acid-catalyzed production of 5-hydroxymethylfurfural (hmf) from glucose
US20190161463A1 (en) * 2016-08-17 2019-05-30 University Of Delaware An integrated process for direct saccharification and dehydration of intact biomass to furfurals

Patent Citations (2)

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US20130150595A1 (en) * 2011-12-07 2013-06-13 James A. Dumesic Lewis and bronsted-lowry acid-catalyzed production of 5-hydroxymethylfurfural (hmf) from glucose
US20190161463A1 (en) * 2016-08-17 2019-05-30 University Of Delaware An integrated process for direct saccharification and dehydration of intact biomass to furfurals

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GUO WENZE; ZHANG ZHENG; HACKING JASPER; HEERES HERO JAN; YUE JUN: "Selective fructose dehydration to 5-hydroxymethylfurfural from a fructose-glucose mixture over a sulfuric acid catalyst in a biphasic system: Experimental study and kinetic modelling", CHEMICAL ENGENEERING JOURNAL, ELSEVIER, AMSTERDAM, NL, vol. 409, 26 December 2020 (2020-12-26), AMSTERDAM, NL , XP086478986, ISSN: 1385-8947, DOI: 10.1016/j.cej.2020.128182 *
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