Exhibit 2021
`E.I. du Pont de Nemours & Co. and
`Acher-Daniels-Midland Co. v. Furanix Technologies B.V.
`IPR2015-01838
`
`1
`
`

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`Gold-Catalyzed Aerobic Oxidation of 5-HMF
`
`butylketone (MIBK) medium as well as in pure organic solvent
`with metal-doped unsupported/TiO2-supported VPO catalysts
`under an oxygen pressure of 1 MPa.[12] For the mixed solvent
`system the yield remained lower than 10 % (3 10 % HMF con-
`version; 60 100 % selectivity) whereas better conversion rates
`and selectivities were obtained in MIBK alone (98 % conver-
`sion; 50 % selectivity) or in other low-polarity organic solvents
`(e.g., benzene, toluene). Yields of up to 81 % (conversion 84 %;
`selectivity 97 %) were obtained in the polar solvent dimethyl-
`formamide.
`The above-described compound DFF is often used as an in-
`termediate for
`the production of FDA. However, catalytic
`routes that lead to the formation of FDA without isolating DFF
`as an intermediate have also been reported.[13] Ribeiro and
`Schuchardt obtained FDA from fructose in 71 % yield via HMF
`formation (72 % conversion from fructose; 99 % selectivity)
`using silica-encapsulated cobalt acetylacetonate as a bifunc-
`tional acid-redox catalyst at 160 8C and an air pressure of
`2 MPa.[14] Furthermore, Lilga et al. have recently patented an in-
`dustrially promising method to oxidize HMF to FDA in up to
`98 % yield (100 % conversion; up to 98 % selectivity) at 100 8C
`and 1 MPa oxygen pressure using a Pt/ZrO2 catalyst.[15]
`In addition to the catalyst systems described above, gold
`has also been found to be an excellent catalyst for the oxida-
`tion of both aromatic and aliphatic alcohols to their corre-
`sponding acids or esters with oxygen as the oxidant under
`benign conditions.[16 25] Recently, aerobic oxidation of HMF in
`methanol with titanium dioxide-supported gold nanoparticles
`was reported by Taarning et al. to give 2,5-furandimethylcar-
`boxylate in 98 % selectivity and 60 % isolated yield at 130 8C
`105 Pa) and added
`using an oxygen pressure of 4 bar (1 bar
`base (sodium methoxide) as the promoter.[23] In contrast, while
`the promoting effect of base on the aqueous-phase oxidation
`of glycerol and CO has been described,[17] no report to date
`has described the base-promoted oxidation of aqueous HMF
`by gold catalysts.
`Accordingly, we have in this work examined the aerobic oxi-
`dation of HMF in basic aqueous solution at ambient tempera-
`ture using a commercial heterogeneous Au/TiO2 catalyst. More
`specifically, the influences of the oxidant (dioxygen) pressure
`and the amount of hydroxide base on the selectivity and yield
`of the reaction are reported, along with a hypothesis on the
`oxidation pathway.
`
`Results and Discussion
`
`Initially, the oxidation of HMF was performed with 20 equiva-
`lents of sodium hydroxide at 20 bar oxygen pressure (ca.
`8 mmol) at 30 8C (Scheme 2 a). The oxidation reaction was fol-
`lowed by using HPLC to measure the concentration of the re-
`action products (with acidic eluent to obtain the FDA).
`The measured yields of all observed reaction products are
`plotted against the reaction time (HMF was fully converted) in
`Figure 1. HMF initially underwent relatively fast oxidation to 5-
`hydroxymethyl-2-furancarboxylic acid (HMFCA) before being
`further oxidized to FDA (Scheme 2 b), as also previously found
`in methanol solution.[23] Thus, no indication supporting a reac-
`
`
`/H2O, P(O2) = 20 bar,
`Scheme 2. a) Oxidation of HMF to FDA. 1) Au/TiO2, OH
`30 8C; 2) H +. b) Possible route for the HMF oxidation reaction via initial oxi
`dation of the formyl group.
`
`Figure 1. Product formation as a function of reaction time in the oxidation
`of HMF by dioxygen in aqueous solution using 1 wt % Au/TiO2 catalyst (20
`equiv NaOH, 20 bar O2, 30 8C; FDA: &, HMFCA: *). Lines were added to
`guide the eye.
`
`tion route involving initial oxidation of the HMF alcohol group
`due to stabilizing electron effects of the furan ring and formyl
`group, as claimed by Vinke et al.,[10] was found under these re-
`action conditions.
`An 18 h control reaction conducted under an inert nitrogen
`atmosphere in the absence of dioxygen (but with all other re-
`action conditions unchanged) also resulted in full HMF conver-
`sion, but with product yields of 51 % HMFCA, 38 % 2,5-dihy-
`droxymethylfuran (DHMF), and 11 % levulinic acid (LA). This
`result suggests that under the generally applied reaction con-
`ditions byproducts form partly by the Cannizzaro reaction (dis-
`proportionation of HMF into HMFCA and DHMF[15]) and partly
`by HMF degradation, thereby limiting the available FDA yield.
`Hence, under optimized conditions a maximum FDA yield of
`71 % was obtained after 18 h of reaction.
`Interestingly, HMF
`degradation apparently resulted in LA formation in the ab-
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`ChemSusChem 2009, 2, 672 675
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`www.chemsuschem.org
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`673
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`sence of oxidant while traces of formic acid (FA) were exclu-
`sively formed in the presence of dioxygen (vide infra).
`HMF was also oxidized in the presence of various amounts
`of NaOH in the reaction mixture, as shown in Figure 2. The use
`of aqueous KOH gave identical results.
`
`ined at both lower and higher oxygen pressures (10 and
`30 bar, respectively; Figure 3).
`As shown in Figure 3, an initial increase in the oxygen pres-
`sure from 10 to 20 bar (or 30 bar) markedly increased the for-
`mation of FDA relative to HMFCA (from 43 % to 71 %), whereas
`
`A. Riisager et al.
`
`Figure 2. Product formation as a function of the introduced amount of base
`(NaOH) in the oxidation HMF by dioxygen in aqueous solution using 1 wt %
`Au/TiO2 catalyst (20 bar O2, 30 8C, 18 h; FDA: &, HMFCA: *). Lines were
`added to guide the eye.
`
`Figure 3. Product formation in as a function of the oxidant pressure in the
`aerobic oxidation of HMF in aqueous solution using 1 wt % Au/TiO2 catalyst
`(20 equiv NaOH, 30 8C, 18 h; FDA: &, HMFCA: *). Lines were added to guide
`the eye.
`
`In reactions with low amounts of added NaOH base
`(2.5 equiv.) the yield of the intermediate oxidation product
`(HMFCA) was high relative to FDA, resulting only in a moder-
`ate yield of FDA at full HMF conversion. In contrast, the con-
`version of HMF was only 13 % without added base (12 % and
`1 % yields of HMFCA and FDA, respectively), suggesting deacti-
`vation of the gold catalyst by the initially formed acids as also
`previously reported for alcohol oxidation in a methanol solu-
`tion.[25] Additionally, precipitation of the formed FDA onto the
`catalyst surface may also have hampered the reaction signifi-
`cantly in the absence of base, where the solubility of FDA is
`quite low.[15]
`The formation of byproducts was largely avoided at all ex-
`amined base concentrations (for both NaOH and KOH), with
`only traces of up to 3 % FA being observed at the higher base
`concentrations examined along with FDA and HMFCA yields of
`about 70 % and 25 %, respectively. Unexpectedly, LA was not
`observed, in contrast to what is usually found when HMF is de-
`graded by rehydration in aqueous acidic medium.[2, 6] Moreover,
`no conversion was observed under the applied reaction condi-
`tions when LA was introduced as a substrate in place of HMF.
`This suggests that the trace of FA generated from HMF degra-
`dation was formed by a route that does not involve LA forma-
`tion. A possible route could involve peroxides generated in
`situ from oxygen, which have also been found to induce by-
`product formation by CC bond cleavage in the gold-catalyzed
`aerobic oxidation of aqueous glycerol.[16, 17] This would also ex-
`plain why FA was not formed in the absence of dioxygen (vide
`supra).
`In addition to the reactions described at 20 bar oxygen pres-
`sure (vide supra), reactions with added NaOH were also exam-
`
`full HMF conversion was achieved at all pressures. This indi-
`cates that an insufficient amount of oxygen was dissolved to
`facilitate the full reaction at 10 bar. Furthermore,
`it confirms
`that the aldehyde moiety of HMF is more easily oxidized than
`the hydroxymethyl group (thereby leading to initial formation
`of HMFCA), in accordance with previous findings for analogous
`oxidations performed in methanol.[24] As no intermediate DFF
`product was observed during the reaction,
`it further implies
`that the final aldehyde oxidation step from DFF to FDA is
`faster
`than the initial aldehyde oxidation, as
`shown in
`Scheme 2 b.
`Upon reuse (after filtration and drying) the catalyst used in
`the reaction at 20 bar with 20 equiv. of added base yielded a
`lower activity towards the oxidation, resulting in a 5 10 %
`lower HMFCA conversion at comparable reaction times. Analy-
`sis of the post-reaction mixture by inductively coupled plasma
`(ICP) spectrometry confirmed that this correlated well with
`gold leaching (corresponding to < 4 % of the original metal in-
`ventory).
`
`Conclusions
`
`In the present work the oxidation of aqueous HMF to FDA by
`a heterogeneous supported gold catalyst and oxygen has
`been investigated. Under optimized basic reaction conditions,
`a 1 wt % Au/TiO2 catalyst was found to oxidize HMF into FDA
`in 71 % yield at 30 8C in 18 h with 20 bar oxygen. Lower pres-
`sures or low concentrations of base (i.e., corresponding to less
`than five equivalents) afforded relatively more of the inter-
`mediate oxidation product HMFCA compared to FDA. Ob-
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`674
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`ChemSusChem 2009, 2, 672 675
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`3
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`

`
`Gold-Catalyzed Aerobic Oxidation of 5-HMF
`
`served traces of FA were proposed to originate, in part, from
`peroxide degradation of the initially formed LA produced by
`HMF rehydration, while base prevented deactivation of the
`gold catalyst and possibly also stabilized the FDA product in
`its anionic form.
`The reaction procedure introduced in this work involves
`HMF oxidation at ambient temperature using an abundant and
`environmentally friendly oxidant and solvent. When combined,
`these features make the protocol an interesting alternative to
`oxidation reactions based on stoichiometric amounts of heavy
`metal oxidants (e.g., chromium and manganese oxygenates)
`that have traditionally been applied to the oxidation of sub-
`strates with similar functionalities.[26] Further development of
`the catalyst system to circumvent the significant metal leach-
`ing and thus improve catalyst durability is in progress.
`
`Experimental Section
`
`(> 99 %),
`levulinic acid (98 %),
`Materials: 5 hydroxymethylfurfural
`formic acid (98 %), sodium hydroxide (> 98 %), and potassium hy
`droxide (> 98 %) were acquired from Sigma Aldrich. 2,5 furandicar
`boxylic acid (> 99 %) and 5 hydroxymethyl 2 furancarboxylic acid
`(> 99 %) were purchased from Toronto Research Chemicals Inc. and
`dioxygen (99,5 %) was obtained from Air Liquide Denmark. All
`chemicals were used as received. For the oxidation reactions a
`commercial 1 wt % Au/TiO2 catalyst was used (Mintek, Brunauer
`1), which by high resolu
`Emmett Teller (BET) surface area 49 m2 g
`tion transmission electron microscopy analysis (JEM 2000FX micro
`scope, 300 kV; sample mounted on a 300 mesh copper grid coated
`with holey carbon film) was found to contain gold particles with
`an average size of 4 8 nm.
`
`Oxidation reactions: Oxidations were carried out in a stirred Parr
`minireactor autoclave equipped with internal thermocontrol (T316
`steel, Teflon beaker insert, 25 mL). In each reaction the autoclave
`was charged with 126 mg of HMF (1 mmol) and a solution of alkali
`hydroxide (0.1 0.8 g, 2.5 20 mmol) in 10 mL water. Subsequently,
`1 wt % Au/TiO2 catalyst was added (0.197 g, 0.01 mmol Au) and the
`autoclave was flushed and then pressurized with dioxygen (10
`30 bar, ca. 4 12 mmol) and maintained at 30 8C for a given period
`under stirring (800 rpm). After the reaction, the autoclave was
`cooled to room temperature (i.e., 20 8C) and after filtering off the
`catalyst a sample was taken out for HPLC analysis (Agilent Technol
`ogies 1200 series, Aminex HPX 87H column from Bio Rad,
`1, solvent 5 mm H2SO4,
`300 mm ” 7.8 mm ” 9 mm, flow 0.6 mL min
`temperature 60 8C). Reference samples were used to quantify the
`products. Reported results are averaged data (< 7 % absolute error)
`obtained from 2 3 separate reactions with an apparent carbon
`mass balance of > 90 % (no CO2 product observed by TCD GC anal
`ysis). ICP analysis (Perkin Elmer ELAN 6000 with cross flow nebuliz
`er and argon plasma) was performed on the diluted post reaction
`1,
`mixture and quantified with an ICP standard solution (1.000 g L
`Fluka).
`
`Acknowledgements
`
`The authors thank Prof. J. E. T. Andersen (Department of Chemis-
`try, Technical University of Denmark) for ICP measurements. This
`work was supported by The Danish National Advanced Technolo-
`gy Foundation and Novozymes A/S.
`
`Keywords: biomass · gold · oxygen · supported catalysts ·
`titania
`
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`Received: February 22, 2009
`
`ChemSusChem 2009, 2, 672 675
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` 2009 Wiley VCH Verlag GmbH & Co. KGaA, Weinheim
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`www.chemsuschem.org
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