Synthesis of Furandicarboxylic Acid Esters From Nonfood Feedstocks Without Concomitant Levulinic Acid Formation

Article abstract of DOI:10.1002/cssc.201700051

5-Hydroxymethylfurfural (HMF) is a versatile intermediate in biomass conversion pathways. However, the notoriously unstable nature of HMF imposes challenges to design selective routes to chemicals such as furan-2,5-dicarboxylic acid (FDCA). Here, a new strategy for obtaining furans is presented, bypassing the formation of the unstable HMF. Instead of starting with glucose/fructose and thus forming HMF as an intermediate, the new route starts from uronic acids, which are abundantly present in many agro residues such as sugar beet pulp, potato pulp, and citrus peels. Conversion of uronic acids, via ketoaldonic acids, to the intermediate formylfuroic acid (FFA) esters, and subsequently to FDCA esters, proceeds without formation of levulinic acid or insoluble humins. This new route provides an attractive strategy to valorize agricultural waste streams and a route to furanic building blocks without the co-production of levulinic acid or humins.

Full text of DOI:10.1002/cssc.201700051

Accepted Article
Title: Synthesis of FDCA-esters without concomitant levulinic acid
formation, starting from non-food feedstocks.
Authors: Frits van der Klis, Jacco van Haveren, Daan S. van Es, and
Harry Bitter
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ChemSusChem
10.1002/cssc.201700051
FULL PAPER
Synthesis of FDCA-esters without concomitant levulinic acid
formation, starting from non-food feedstocks.
[a,b]
[b]
[b]
[a]
Frits van der Klis , Jacco van Haveren , Daan S. van Es* and Johannes H. Bitter*
Abstract: 5-(Hydroxymethyl)-furfural (HMF) is
a
versatile
production. For example commercial D-fructose resources are
high fructose syrups, which are generally produced from starch-
intermediate in biomass conversion pathways, however the
notoriously unstable nature of HMF imposes challenges to design
selective routes to chemicals like furan-2,5-dicarboxylic acid (FDCA).
Here we present a new strategy for obtaining furans, bypassing the
formation of the unstable HMF. Instead of starting with
glucose/fructose and thus forming HMF as an intermediate, the new
route starts from uronic acids, which are abundantly present in many
agro residues like e.g. sugar beet pulp, potato pulp, citrus peels, etc.
Conversion of uronic acids, via ketoaldonic acids, to the intermediate
formylfuroic acid esters (FFA-esters), and subsequently FDCA-
esters, proceeds without formation of levulinic acid and insoluble
humins. This new route therefore provides an attractive strategy to
valorize agricultural waste-streams, and a route to furanic building
blocks without the co-production of levulinic acid and insoluble
humins.
[
5]
containing food crops like corn. To eliminate the conflict with
food production, a route to FDCA should be developed starting
from non-food lignocellulosic feedstocks like wood or grasses, or
even more preferably from the residues of agro-food production.
This prompted us to explore the potential of obtaining FDCA-
esters via an alternative approach, not starting from
glucose/fructose, and circumventing the intrinsic instability of
HMF.
We propose 2-formyl-5-furoic acid esters (FFA-esters) as an
alternative to HMF (Scheme 1): We hypothesize that due to the
lack of a primary alcohol function in FFA-esters, that FFA-esters
are more stable than HMF, because acidic dehydration
[
2-
pathways and subsequent levulinic acid formation are blocked.
3
]
Subsequent catalytic oxidation of FFA-esters will yield the
desired FDCA-esters.
Scheme 1 shows an overview of the new proposed route to
FDCA-esters: If FFA-esters are the desired intermediates
towards FDCA-esters, this requires also a higher oxidation state
of the carbohydrate starting materials: 5-Keto-aldonic acids (5-
KA’s) are the retro-synthetic precursor for FFA-esters
Introduction
One of the most promising examples of biobased building blocks
is furan-2,5-dicarboxylic acid or FDCA, which has many potential
applications like polyesters, polyamides and plasticizers. The
majority of research in FDCA production focusses on the use of
hexose sugars (i.e., D-glucose and D-fructose) which are first
dehydrated to the intermediate HMF, followed by an oxidation
to FDCA (Scheme 1).
Currently, the main challenge for the efficient synthesis of furans
from sugars is the intrinsic instability of the intermediate 5-
hydroxymethylfurfural (HMF). Under the acidic aqueous
conditions applied, HMF is easily re-hydrated forming levulinic
(
analogous to the dehydration of D-fructose to HMF). Uronic
acids would then be the retro-synthetic precursors for 5-KA’s
analogous to the isomerization of D-glucose to D-fructose).
Both FDCA and FDCA-esters can be used in polyester synthesis
currently the largest potential application area of FDCA)
[
1]
(
[
2]
(
analogous to the use of terephthalic acid and dimethyl-
terephthalate, which are both used in the industrial synthesis of
[7]
PET.
The proposed route is also implementable on industrial scale:
uronic acids are present in various large agro-residue streams.
D-Galacturonic acid is the most abundant uronic acid, and is the
main constituent of pectin. Pectin is found in large amounts in
sugar beet pulp (contains 900.000 ton D-galacturonic acid,
[
2-3]
acid and formic acid.
Furthermore, (insoluble) humins can be
[
4]
formed in high amounts. All these side reactions do not only
lead to losses in desired HMF, but also require the valorization
of levulinic acid and humin side products to make the overall
route economically viable.
Alternative routes have been developed in which more stable
HMF-ethers are formed. However, still humin formation occurs
and alkyl-levulinates are formed as a by-product.
A second disadvantage of using HMF as an intermediate relates
to the feedstock used to make the HMF. Currently it is made
from glucose and/or fructose, which both interfere with food
[8]
[9]
worldwide), chicory pulp, fruit peels like citrus peels (375.000
[
5]
[10]
ton D-galacturonic acid, worldwide),
200.000 ton D-galacturonic acid, US / 7.100 ton UK ), and
coffee pulp (~30.000 ton D-galacturonic acid, worldwide).
potato peels/pulp
[11]
[12]
(
[
6]
[13]
[
5]
As an example, efforts are being undertaken to scale up the
commercial production of D-galacturonic acid from sugar beet
[14]
pulp.
D-Glucuronic acid is the second important readily available
[
15]
[16]
uronic acid, and is found in xanthan gum,
gum arabic,
[
17]
wheat bran,
various types of soft- and hardwoods.
and is one of the main pectin constituents in
[
18]
[
a]
F. van der Klis, Prof. Dr. J. H. Bitter
Wageningen University Biobased Chemistry and Technology
Bornse Weilanden 9, 6708WG Wageningen, The Netherlands
E-mail: harry.bitter@wur.nl
Three other uronic acids are present in nature, for example in
macro algae: D-mannuronic acid, L-guluronic acid and L-iduronic
[
15, 19]
[
b]
F. van der Klis, Dr. J. van Haveren, Dr. D. S. van Es
acid.
However, these have to be obtained by hydrolysis of
Wageningen Food & Biobased Research
Bornse Weilanden 9, 6708WG Wageningen, The Netherlands
E-mail: daan.vanes@wur.nl
alginates, which is currently still challenging. Therefore, these
uronic acids are not yet readily available.
[20]
Supporting information for this article is given via a link at the end of the
document.
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ChemSusChem
10.1002/cssc.201700051
FULL PAPER
Scheme 1. Comparison of the traditional approach from glucose to FDCA-(esters), with the alternative route starting from uronic acids.
Overall, there is already a significant stream of non-edible uronic
acids available (>1.5M ton of D-galacturonic acid alone), which
can serve as 2 generation, non-food based, starting materials
disadvantage of working in very dilute reaction mixtures. Here
we used a more soluble calcium precursor (CaCl ), which
allowed to work in more concentrated solutions. This resulted in
an increase of the yield of 5-keto-L-galactonic acid from 46% for
2
nd
for furans like FDCA.
Here we present a new catalytic 3-step route to 2 generation
nd
Ca(OH)
2 2
to 82% when CaCl was used. (see experimental
FDCA: Step 1) Isomerization of uronic acids to their
corresponding 5-keto-aldonic acids. Step 2) Acid catalyzed
cyclodehydration to FFA(-esters). Step 3) Oxidation to FDCA(-
esters).
section).
We then moved from D-galacturonic acid to the second
important uronic acid: D-glucuronic acid was isomerized in the
presence of CaCl
2
to give 5-keto-D-mannonic acid (IUPAC
name: D-lyxo-Hex-5-ulosonic acid) in 42% isolated yield after
filtration of the reaction mixture. TLC-Analysis of the filtrate
revealed the presence of residual product, apparently caused by
the higher aqueous solubility of 5-keto-D-mannonic acid. The
Results and Discussion
Isomerization (step 1)
2
use of CaCl has the advantage of obtaining selectively one of
the isomers, further optimization is needed to maximize the yield.
As discussed above, the first step in our proposed process is the
isomerization of uronic acids to their corresponding 5-keto-
aldonic acids (step 1 in Scheme 1). This reaction can be
Out of the five naturally occurring uronic acids, only three
different 5-keto-aldonic acids can be prepared (for a detailed
explanation, see Figure S1 in supplementary information). Two
of those 5-keto-aldonic acids were prepared as discussed above.
The third one, 5-keto-D-gluconic acid, (IUPAC name: D-xylo-
Hex-5-ulosonic acid) is commercially available as it is one of the
[
21]
performed by different microorganisms and enzymes,
as has
been shown for the conversion of D-galacturonic acid to 5-keto-
L-galactonic acid (IUPAC name: D-arabino-Hex-5-ulosonic
[22]
acid). In addition, chemical isomerization of uronic acids to 5-
keto-aldonic acids in alkaline medium has been shown as
[
26]
[
23]
intermediates in vitamin-C production via fermentation.
well.
This is the so-called Lobry de Bruyn–van Ekenstein
[
24]
Therefore, all three possible 5-keto-aldonic acids are available
for the second step: the cyclodehydration to 5-formyl-furoic acid
esters (FFA-esters).
transformation.
Unfortunately these isomerization methods result in equilibrium
mixtures that contain only a limited fraction of the desired
product (e.g. D-galacturonic acid : 5-keto-L-galactonic acid = 34 :
[
21c]
6
6).
adapted a procedure of Ehrlich and Guttmann
that 5-keto-L-galactonic acid could be selectively precipitated by
To shift the equilibrium to the desired products, we
[
25]
who showed
2
+
2
Ca . These authors used poorly soluble Ca(OH) , which has the
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ChemSusChem
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Cyclodehydration (step 2)
Clearly the ring conformation of the carbohydrate has a marked
influence on the Me-FFA yield. The uronic acids are mainly in
the 6-membered ring pyranose form in water (D-galacturonic
Keto-aldonic acid vs uronic acid
[
29]
The second step is the cyclodehydration of 5-keto-aldonic acids
to FFA-esters (step 2 in Scheme 1). Table 1 displays an
overview of the yield of the desired Me-FFA starting from the
three 5-keto-aldonic acids (entry 1-4) and uronic acids (entry 5-
acid: ~90%).
membered furans, giving undesired degradation instead.
However, the related 5-keto-L-galactonic acid adapts almost
exclusively (>99%) furanose conformation (5-membered
The other two 5-keto-aldonic acids also prefer a 5-
membered ring conformation i.e. >99% for 5-keto-D-mannonic
This prevents direct cyclodehydration to 5-
[
30]
a
[
31]
7).
ring).
5-Keto-D-gluconic acid (K-salt) was reacted in methanolic HCl, to
[
32]
give the expected Me-FFA in 43% crude yield (Table 1, entry 1),
thereby confirming previous results of Votocek (40% crude
acid and 80-89% for 5-keto-D-gluconic acid. The remainder is
[
32-33]
in the open chain or lactone form
.
[
27]
yield).
The same conditions were applied to 5-keto-L-
The effect of the ring conformation on reactivity has been
observed before for the conversion of glucose/fructose to HMF.
The highest yields of HMF are achieved starting from D-fructose,
which has a higher preference for the furanose form (5-
membered ring) in aqueous solution (~25%), while D-glucose is
galactonic acid (CaOH-salt), which gave Me-FFA in 50-65%
crude yield (Table 1, entries 2-3). This yield is significantly
higher than previously reported yields (11% after purification) by
[
28]
Stutz et al., and more in line with the results obtained with 5-
[
34]
keto-D-gluconic acid (K-salt). Also, 5-keto-D-mannonic acid
only for 1% in the furanose form. Although still under debate,
it is thought that due to its furanose configuration D-fructose
dehydrates more efficiently to HMF, which is also a 5-membered
(
mixed Ca/Na-salt) (Table 1, entry 4) could be converted to the
desired product although in a somewhat lower yield (17%).
Please note we did not study the influence of the cation (K / Ca).
These initial results show that the conversion of all three 5-keto-
aldonic acids to FFA-esters is possible.
[
2, 35]
ring.
in
It is also believed that the fructo-furanose form results
decrease in competitive pathways during
Here we found a similar effect for the
a
[
36]
cyclodehydration.
converion of uronic acids (6 membered ring) vs keto-aldonic
acids (5 membered ring).
Table 1. Cyclodehydration of various 5-keto-aldonic acids and uronic acid
[
a]
derivatives in MeOH/HCl.
Influence of the nature of the acid
Entry
Substrate
Reaction
time (h)
Crude Me-FFA
The discussed experiments of Table 1 were all performed in
methanolic HCl, but for practical reasons we wanted to switch to
acids that are less corrosive, less volatile and easier to dose. A
[
b]
yield (mol%)
1
2
3
4
5
6
7
5-keto-D-gluconic acid (K-salt)
5-keto-L-galactonic acid (CaOH-salt)
5-keto-L-galactonic acid (CaOH-salt)
5-keto-D-mannonic acid (Ca/Na-salt)
D-galacturonic acid (monohydrate)
D-galacturonic acid (Na-salt)
72
72
24
24
24
24
24
43
50
65
17
0
2 4 3 4
small screening of such acids (H SO , H PO , methane sulfonic
acid (MSA) and p-toluenesulfonic acid (p-TSA)) showed that the
best initial results were obtained using MSA (6-12 equivalents).
The next part of this investigation will discuss the most important
reaction parameters.
<1
<1
D-glucuronic acid
[
a] Conditions: 1.0 g substrate in 10 mL 3N MeOH/HCl, 65 ˚C. [b] Isolated
Table 2 shows an overview of all results on the conversion of 5-
keto-L-galactonic acid (analogues) under varying reaction
conditions. The following sub-chapters will deal with the most
important factors: 5-Keto-aldonic acid vs fructose conversion,
stability of intermediates, mass balance, influence of water, and
the influence of solvent. It was also decided to isolate and purify
yield of product after extraction without purification (purity ~90-100% based on
GC and NMR).
To verify if the isomerization of uronic acids to 5-keto-aldonic
acids (step 1 Scheme 1) is a necessary step, the conversion of
uronic acids was investigated under the same reaction
conditions.
(
silica column chromatography) the products of all further
experiments, to facilitate fair comparisons.
When starting from D-galacturonic acid, the parent uronic acid of
5-keto-L-galactonic acid, no Me-FFA was formed (Table 1,
5-Keto-aldonic acid vs fructose conversion
entries 5 (monohydrate form) and 6 (Na-salt)). Instead of Me-
FFA, methyl (methyl galactosid)uronates were the only
detectable products (See figure S4). Similar results were
obtained when starting from D-glucuronic acid, the parent uronic
acid of 5-keto-D-mannonic acid, i.e. no yield of Me-FFA (Table 1,
entry 7).
To indicate the advantage of the FFA-esters vs the HMF route
with respect to product- and side-product formation, we
compared the conversion of 5-keto-L-galactonic acid (Table 2,
entry 1) with the conversion of D-fructose (Table 2, entry 6).
Starting from 5-keto-L-galactonic acid, Me-FFA was isolated in
49% purified yield after flash column chromatography (Table 2,
To summarize, the (un-optimized) conversion of all three
possible 5-keto-aldonic acids gave Me-FFA in reasonable yields
entry 1). The crude product before purification had already a
good purity (>90%), while no levulinic acid (ester) was present,
and the amount of insoluble humins in the reaction mixture was
very limited (<5 wt%, too little to isolate during workup). This in
contrast to a reaction starting from D-fructose, which instead of
(
17-65%). However, the parent uronic acids gave <1% Me-FFA
under the same reaction conditions, showing that the
isomerization of aldose to the ketose species is required to
achieve an effective cyclodehydration.
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ChemSusChem
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FULL PAPER
[
a]
Table 2. Cyclodehydration of 5-keto-L-galactonic acid (analogues) and product stability in various alcohols.
[
b]
[c]
Entry
Substrate
Alcohol
Water removal
Time (h)
Temp. (˚C)
Intended Product
Purified yield (mol%)
1
2
3
4
5
6
7
8
9
5-KG.CaOH
5-KG.CaOH
5-KG.CaOH
Me-FFA
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
No
24
24
24
24
24
24
18
18
24
24
65
65
65
65
65
65
78
78
97
97
Me-FFA
Me-FFA
Me-FFA
Me-FFA
HMF
49
48
38
78
Yes
+6 eq. H
No
2
O
[
[
d]
d]
HMF
No
<2
<1
50
55
43
45
D-Fructose
5-KG.CaOH
5-KG.CaOH
5-KG.CaOH
5-KG.CaOH
No
HMF
No
Et-FFA
Et-FFA
Pr-FFA
Pr-FFA
EtOH
Yes
No
n-PrOH
n-PrOH
10
Yes
[
a] Conditions: 12 mmol substrate in 100 mL MeOH, and 12 equivalents of MSA. [b] Active water removal via Soxhlet setup (yes/no) or deliberate addition
of water. [c] Isolated yield of product after silica gel chromatography (purity >99%). [d] Me-levulinate was isolated as the main product (entry 5: 35 mol%;
entry 6: 39 mol%) and severe insoluble humin formation was observed.
the desired HMF, gave Me-levulinate and humins as the main
products (Table 2, entry 6).
up procedures of the crude reaction mixtures were applied (see
supporting information Figures S5-S7).
NMR and HPLC-MS analyses indicate that, apart from the
desired FFA-esters, the reaction mixture consists of a complex
mixture of glycosides. These glycosides can be further valorized
e.g. by transacetalization with higher alcohols to give surfactants.
A full characterization of this complex mixture falls outside of the
scope of the present study, but will be part of future work.
Stability of the intermediates
These results prompted us to investigate if the stability of Me-
FFA and HMF under our conditions can explain the differences
in product yield. Hereto Me-FFA was stirred for 24h in refluxing
MeOH / MSA to give a clear light yellow reaction mixture. After
workup, Me-FFA was recovered in 78% (Table 2, entry 4). For
comparison HMF was exposed to the same conditions (Table 2,
entry 5). The HMF reaction mixture turned black within 30 min.
and after workup (after 24h) no HMF was recovered. The main
products were Me-levulinate (35 mol%) and insoluble humins.
Figure 1 shows a picture of both reaction mixtures to further
illustrate the difference in stability.
Influence of water
Since water is inevitably formed as a co-product during the
cyclodehydration, we investigated the role of water on
conversion, Me-FFA selectivity, and humin formation. From one
mole of 5-keto-aldonic acid (CaOH-salt) a maximum of six moles
of water is formed (step 2 in Scheme 1).
Hence, the presence of substituents with a high oxidation state
We investigated the influence of water on the cyclodehydration
in two ways: first by deliberately adding water to the reaction
mixture and second by actively removing water during the
reaction (Table 2, entries 1-3).
Addition of 6 equivalents of water to the substrate resulted in a
decrease in Me-FFA yield from 49% to 38% (Table 2, entries 1
and 3). Moreover visual inspection of the reaction mixture
indicated that the amount of insoluble humins also increased
(visual observation only, as accurate gravimetric analysis is
hampered by the presence of salts).
(
aldehyde and carboxylic acid) on the FFA furan ring have
significantly reduced the propensity for acid catalyzed hydration,
and subsequent formation of levulinic acid and humins,
[
2]
compared to HMF.
Mass balance
While under our conditions we did not observe any levulinic acid
formation from the 5-keto-aldonic acids (neither by NMR, GC-
MS or HPLC analysis) the isolated yields were less than 100%
at 100% conversion. This indicates that side products were
formed. To identify these products, and obtain insight into the
competitive reaction pathways, alternative (non-aqueous) work-
Although water and methanol do not form an azeotrope, we tried
to actively remove water by applying a Soxhlet setup filled with
3Å molsieves. However, the purified yield of Me-FFA did not
change (49-48%, Table 2, entries 1 and 2) in methanol.
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FFA-esters were oxidized according to a previously reported
[
38]
Influence of solvent
procedure.
Me-FFA and Et-FFA were oxidized in methanol,
We then investigated the influence of water removal for two
higher alcohols: ethanol and propanol. Since these alcohols do
form azeotropes with water, the water removal should be more
efficient in the Soxhlet setup. Another effect of changing to other
solvents under reflux is the increased reaction temperature.
using 10 mol% NaOMe as base. The reactions were performed
at RT, using a 1:344 gold to substrate ratio, and 5 bar oxygen
overpressure. Both Me-FFA and Et-FFA gave full conversion to
dimethyl-FDCA in 99+% selectivity in 22 h.
The main advantage of FFA-ester oxidation compared to the
oxidation of HMF, is that the oxidation of the primary alcohol is
5-Keto-L-galactonic acid (CaOH-salt) was reacted in ethanol with
2 equivalents of MSA for 18h, with and without active water
[
39]
1
often the most challenging in HMF oxidation.
This primary
removal (Table 2, entries 7-8). The purified yields of Et-FFA (50-
5%) of both reactions were slightly higher compared to the
reactions in methanol (48-49% Me-FFA, Table 2, entries 1-2),
indicating an advantageous effect of temperature. The increased
yield during active water removal in ethanol shows the
alcohol is present in HMF, but in contrast, in FFA-esters only the
more reactive aldehyde functionality has to be oxidized, which
can apparently be performed under very mild conditions.
5
detrimental effect of water on the selectivity of the dehydration Conclusions
reaction.
To further investigate the effect of solvent on the conversion of
-keto-L-galactonic acid, also 1-propanol was used. In 1-
propanol, without active water removal, Pr-FFA was isolated in
3% purified yield (Table 2, entry 9). Removal of the water
slightly increased the purified yield of Pr-FFA to 45% (Table 2,
entry 10).
In conclusion, we have shown that abundantly available uronic
acids (potentially >1.5 M ton/annum from 2 generation, non-
nd
5
food feedstock) can be converted into (dimethyl)FDCA via a
novel 3-step catalytic route, in an overall unoptimized isolated
yield of 45%, which is competitive with routes starting from
glucose. In the first step, uronic acids are isomerized in alkaline
4
2
+
To summarize: the cyclodehydration of all 5-keto-aldonic acids
gave the desired FFA-esters in moderate to good isolated yields
water in the presence of Ca , leading to the selective
precipitation of 5-keto-aldonic acids at RT. In the second step,
we have shown that 5-keto-aldonic acids can be converted into
FFA-esters via a mild cyclodehydration in alcoholic solvents in
the presence of an acid catalyst. Control experiments showed
that uronic acids did not give FFA-esters as product, proving the
necessity of the isomerization step. During the conversion of 5-
keto-aldonic acid to FFA-esters, no levulinic acid and only
limited insoluble humin formation was observed. In the third and
final step, FFA-esters were converted to dimethyl FDCA via a
mild Au-catalyzed oxidation reaction, at RT and using only
molecular oxygen as the oxidant. Hereby we have demonstrated
that this new route from agro residue derived feedstocks like
sugar beet pulp or citrus peels is an attractive strategy for the
(
17-55%). The best yields are obtained in ethanol with
continuous removal of water. Although further optimization is
required, the isolated yield after column chromatography (55%)
is already quite high, and competitive with HMF yields starting
[
37]
from glucose (realistic process yields are around 55%).
nd
production of 2 generation FDCA and derivatives.
Experimental Section
Materials
Figure 1. Appearance of reaction mixtures during stability tests: Left: Me-FFA
after 24 h reaction time), Right: HMF (after 30 min. reaction time). Reaction
The following chemicals, solvents and gasses were used without further
purification: acetic acid (100%, GPR RECTAPUR, VWR Chemicals);
activated carbon (SX1G, Norit); ammonia solution (ACS reagent, Sigma
Aldrich); ammonium nitrate (>99.0%, Sigma Aldrich); calcium chloride
(
conditions: Substrate (12 mmol), methanol (100 mL), MSA (12 eq.), reflux.
(
dehydrated, purum, >97%, Sigma Aldrich); calcium oxide (fine powder,
Oxidation (step 3)
puriss., Riedel-de Haën); Celite 545 (Sigma Aldrich); chloroform (HPLC,
stabilized with ethanol, min. 99.9%, Actu-All Chemicals); diethyl ether,
The final step in the new route to FDCA is the catalytic oxidation
of FFA-esters to FDCA-esters (step 3 in Scheme 1). Here we
investigated the effectivity of an oxidation using Au/C, a base
and molecular oxygen at RT. The Au/C catalyst contained 1.3
wt% Au with an average gold particle size of 2.2 nm, and was
prepared via cationic adsorption (see Supplemental information
Figure S3).
(
for analysis, Merck); ethanol (absolute, 99.9%, VWR Chemicals); ethyl
acetate (pure, Acros Organics); D-(-)-fructose (>99.0%, Merck); D-
galacturonic acid monohydrate (> 99%, gift from Royal Cosun), D-
galacturonic acid sodium salt monohydrate (purum > 98.0%, Fluka); D-
glucuronic acid (>98%, Sigma Aldrich); gold(III)chloride trihydrate (ACS
reagent, Sigma Aldrich); 5-(hydroxymethyl)furfural (99%, Sigma Aldrich);
5
-keto-D-gluconic acid potassium salt (98%, International Laboratory
USA); magnesium sulphate (dried, with ca 1-2 mol water of hydration,
Alfa Aesar); methanesulfonic acid (>99.5% Sigma Aldrich); methanol (for
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201700051
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analysis, Merck); methanolic HCl, (3N, Supleco); molecular sieves (3Å,
15 mm Ni foil monochromator. The patterns were recorded between 4
beads, 8-12 mesh, Aldrich); oxygen (5.0, Linde Gas Benelux); nitric acid
and 50 °2ϴ using a step-size of 0.02 °2ϴ and a counting time of 5 s.
(p.a., 65%, Sigma Aldrich); petroleum ether (ACS reagent, boiling range
4
0-60 ˚C, Acros Organics); phosphoric acid (>85%, p.a., Sigma Aldrich);
Literature procedure for the preparation of 5-keto-L-galactonic acid
mono-basic calcium salt
1-propanol (ACS reagent, >99.5%, Sigma Aldrich); pyridine (ACS
[25]
reagent, 99.0%, Sigma Aldrich); Sicapent (with indicator, Merck); silica
gel 60 (0.040-0.063 mm, 230-400 mesh, Alfa Aesar); sodium hydrogen
carbonate (99%, Alfa Aesar); sodium hydroxide (pellets, reagent grade,
Calcium oxide (11.18 g, 0.199 mol) was suspended in demineralized
water (10 L) and stirred for 10 min. in an open beaker. A small amount of
un-dissolved particles was removed by filtration, yielding a colorless clear
solution. D-galacturonic acid monohydrate (40.01 g, 0.198 mol) was then
added under stirring to give a clear, slightly yellow solution. After 3 days
at RT, the formed crystals were collected by suction filtration. The initially
transparent crystals were dried to a constant weight under vacuum at 40
>
98%, anhydrous, Sigma Aldrich); sodium methoxide (Sigma-Aldrich);
sulfuric acid (98%, p.a., Merck), p-toluenesulfonic acid monohydrate
98.5%, ACS reagent, Sigma Aldrich).
(
Analytical Equipment
˚C, in the presence of Sicapent. The resulting 5-keto-L-galactonic acid
Thin layer chromatography (TLC) was performed using Silica gel 60 F254
plates (500 Glass plates, 2.5 x 7.5 cm, Merck). All carbohydrates were
analyzed using the following procedure: Mobile phase: ethyl acetate (5) :
pyridine (5) : water (1) : acetic acid (3). An aqueous solution of the
compound was applied on the plate. A few drops of HCl were added to
calcium salts that not dissolve in pure water. The TLC plate was
developed, dried, developed for a second time, dried again, and stained
with 5% sulfuric acid in ethanol. Heating with a heat gun showed the
compounds as black dots. FFA-esters / dimethyl-FDCA: Mobile phase:
ethyl acetate (1) : petroleum ether (9). TLC plates were developed, dried,
followed by detecting of the products under UV (254 nm). HMF and
methyl-levulinate: Mobile phase: petroleum ether (7) : ethyl acetate (3).
The plate was colored using a permanganate stain followed by gentle
heating.
mono-basic calcium salt was obtained as a bright yellow powder (22.9 g,
yield 46 mol%).
TLC: 5-Keto-L-galactonic acid gave a single spot (R
starting D-galactonic acid gave a single spot at a lower R
f
0.39) while the
value (0.32).
f
13
C-NMR (100.62 MHz, D
2
O): δ =62.44 (6β), 63.15 (6α), 66.78 (6γ),
7
7
1
0.43 (4β), 71.55 (4γ), 71.87 (3γ), 72.55 (3β), 72.66 (3α), 73.10 (2γ),
8.09 (4α), 80.08 (2α), 80.88 (2β), 103.52 (5β), 105.68 (5α), 175.26 (1α),
75.53 (1β), 178.41 (1γ), 213.16 (5γ). The NMR is in agreement with
[31]
previously reported values.
Elemental analysis: Measured composition = 29.9% C, 3.27% H, 16.49%
Ca, 0.15% Na, 50.02% O (calculated), Calculated composition = 28.8%
C, 4.03% H, 16.02% Ca, 51.15% O
GC-MS analyses were performed using an Interscience TraceGC Ultra
GC with an AS3000 II auto sampler. Products were separated over a
Restek GC column (Rxi-5ms 30m x 0.25mm x 0.25µm). Helium was used
XRD: (see Supplemental information Figure S2)
-
1
-1
as the carrier gas, with a flow of 1 mLmin , and a split flow of 20 mLmin .
-
1
Improved method for the preparation of 5-keto-L-galactonic acid
mono-basic calcium salt
Temperature program: hold 3 min at 50 °C, ramp 7.5 °Cmin , final
temperature 330 °C. An Interscience TraceDSQ II XL quadrupole mass
selective detector (EI, mass range 35-500 Dalton, 150 ms sample speed)
was used for detection.
Calcium chloride (52.4 g, 0.472 mol) and D-galacturonic acid
monohydrate (100 g, 0.471 mol) were dissolved in demineralized water
(
1.6 L) and stirred for 15 min. in 2.5 L beaker. A small amount of un-
NMR spectra were recorded on a Bruker Avance III spectrometer
1
13
dissolved particles was removed by filtration, yielding a slightly yellow
clear solution. A solution of sodium hydroxide (38 g, 0.95 mol) in water
operating at 400.17 MHz ( H) and 100.62 MHz ( C) in CDCl
atom % D, Aldrich), DMSO-D (99.5 atom % D, contains 0.03% v/v TMS,
Aldrich), MeOD-D (≥99.8 atom % D, contains 0.03 % v/v TMS, Aldrich)
or D O (99.9 atom % D, Aldrich). D O solutions were adjusted to the
desired pH with DCl (35 wt% solution in D O, 99 atom % D, Aldrich) or
NaOD (40 wt% solution in D O, 99+ atom % D, Aldrich). Chemical shifts
3
(99.9
6
(200 mL) was added dropwise over 30 min. under continuous stirring.
4
After the addition of ~50% of the sodium hydroxide, the solution became
more yellow, and solids appeared. After complete addition of the sodium
hydroxide, the mixture was stirred for an additional 6 h at RT. The solid
material was collected by suction filtration, washed with water and dried
to a constant weight under vacuum at 40 ˚C over Sicapent. The resulting
2
2
2
2
are quoted in parts per million (ppm) referenced to the appropriate
solvent peaks or 0 ppm for TMS.
5-keto-L-galactonic acid mono-basic calcium salt was obtained as a
bright yellow powder (96.7 g, yield 82 mol%).
Elemental analysis (carbon, hydrogen, calcium and sodium) was
measured by Mikroanalytisches Laboratorium KOLBE, Mülheim an der
Ruhr, Germany.
TLC was identical to the material prepared via the literature procedure
(
vide supra).
Transmission Electron Microscopy (TEM) and High-Angle Annular Dark-
Field Imaging (HAADF) measurements were performed with a Philips
Tecnai 20 FEG instrument, operating at 200 kV. The catalyst was used
without further treatment and was dispersed in ethanol followed by
deposition on a carbon coated copper grid. The particle size distribution
was determined by measuring the dimensions of 913 particles using
Image-J software.
Elemental analysis: Measured composition = 30.14% C, 3.17% H,
1
2
6.53% Ca, 0.2% Na, 50.14% O (calculated), Calculated composition =
8.8% C, 4.03% H, 16.02% Ca, 51.15% O
XRD: Corresponds to the material prepared via the literature procedure
(see Supplemental information Figure S2)
X-ray Diffraction (XRD) patterns were recorded using a Philips PC-APD
diffractometer with a Cu Kα1 anode operating at 40 mA and 40 kV, and a
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ChemSusChem
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FULL PAPER
1
3
Preparation of 5-keto-D-mannonic acid
C-NMR (100.62 MHz, CDCl
53.87, 158.38, 178.92.
3
): δ = 52.54, 118.63, 118.75, 147.62,
1
Calcium chloride (7.18 g, 64.7 mmol) and D-glucuronic acid monohydrate
1
(15 g, 64.7 mmol) were dissolved in demineralized water (240 mL) and
6
H-NMR (400.17 MHz, DMSO-D ): δ = 9.75 (1 H, s), 7.62 (1 H, d, J = 3.8
stirred for 15 min. in 500 mL beaker to give a clear slightly yellow solution.
A solution of sodium hydroxide (2.59 g, 64.7 mmol) in water (30 mL) was
added dropwise over 15 min. under continuous stirring. After the addition
of the first drops of sodium hydroxide, white solids started to appear.
After complete addition of the sodium hydroxide, the milky mixture was
stirred for 3 days at RT. The solid material was collected by suction
filtration, washed with water and dried to a constant weight under
vacuum at 40 ˚C over Sicapent. The resulting 5-keto-D-mannonic acid
was obtained as a bright yellow powder (6.82 g, ~17 mol%).
Hz), 7.49 (1 H, d, J = 3.8 Hz), 3.88 (3 H, s).
+
MS (GC-MS, 70eV): m/z (%) = 154 (55) [M ], 123 (100), 109 (2), 95 (24),
7 (6), 53 (5), 39 (23).
6
NMR (CDCl
Khusnutdinov et al. , and the NMR in DMSO-D
reported by Shackelford et al. (note that the two furan protons overlap
in deuterated chloroform, while they give two separated signals in
deuterated DMSO)
3
) and MS correspond to previous reported values by
[40]
6
corresponds to values
[41]
TLC: Both the precipitated 5-Keto-D-mannonic acid and the filtrate gave
single spots (R
spot at a lower R
f
0.53) while the starting D-glucuronic acid gave a single
value (0.38).
Methyl 5-formyl-2-furoate (dimethyl acetal):
f
TLC: R
f
value 0.38
13
3
C-NMR (100.62 MHz, CDCl ): δ = 62.91 (6β), 62.93 (6α), 75.90 (4α),
7
8.00 (4α), 79.58 (4β), 80.61 (2α), 81.31 (3β), 81.72 (2β), 102.45 (5α),
1
3
H-NMR (400.17 MHz, CDCl ): δ = 7.16 (1 H, d, J = 3.5 Hz), 6.54 (1 H, d,
105.33 (5β), 177.78 (1β), 178.42 (1α). The NMR (measured in Na-form
[
32]
J = 3.5 Hz), 5.46 (1 H, s), 3.89 (3 H, s), 3.37 (6 H, s).
after ion exchange) is in agreement with previously reported values.
13
C-NMR (100.62 MHz, CDCl3): δ =51.84, 53.02, 97.52, 110.32, 118.33,
Elemental analysis: Measured composition = 26.2% C, 3.4% H, 12.4%
Ca, 2.8% Na, 55.2% O (calculated).
144.27, 155.03, 158.95.
+
MS (GC-MS, 70eV): m/z (%) = 200 (5) [M ], 169 (100), 153 (4), 141 (10),
XRD: see Supplemental information Figure S2
123 (20), 109 (3), 95 (3), 82 (3), 75 (10), 67 (3), 59 (7), 53 (4), 39 (8).
General literature procedure for the cyclodehydration of various 5-
keto-aldonic acids and uronic acid derivatives in MeOH/HCl to Me-
FFA
[
40]
Values correspond to those previously reported by Khusnutdinov et al.
[28a]
Improved general procedure for the preparation of 5-formyl-2-
furoate esters
The following general procedure was used for the experiments reported
in table 1: Round bottom flasks (50 mL) were equipped with magnetic
The following general procedure was used for the experiments reported
in table 2: A 250 mL round bottom flask was equipped with a magnetic
stirring bar and placed on a DrySyn heating plate. The flask was
equipped with a Soxhlet-setup. In experiments with active water removal,
the Soxhlet-setup was filled with dried 3Å molsieves (20 g). In
experiments without active water removal, the Soxhlet-setup was not
filled with molsieves. The round bottom flask was charged with the
desired substrate (12 mmol) and 100 mL alcohol (MeOH, EtOH or
nPrOH). The Soxhlet set-up was filled with another 70 mL of the same
2
stirring bars and reflux condensers with N -inlet. The flasks were charged
with substrate (4 mmol) and methanolic HCl (3N solution, 10 mL). The
substrates dissolved rapidly, to give clear colorless solutions. The
reaction mixtures were heated to reflux (65 ˚C) for 24-72 h. The resulting
clear red-brown solutions were allowed to cool to RT and demineralized
water (10 mL) was added under stirring. After 45 min. the aqueous
mixtures were extracted with diethyl ether (3x 20 mL). The combined
organic layers were then washed with brine until the pH of the water layer
was neutral. The organic layers were dried over MgSO4, filtered and
concentrated at 40 ˚C under vacuum using a rotary evaporator. The
resulting methyl 5-formyl-2-furoate was obtained as a red-brown oil. This
red-brown oil tended to crystallize within a few minutes after cooling to
2 4
alcohol. Acid catalyst (H SO , p-TSA or MSA) was added, and the
reaction mixture was heated to reflux under stirring for the desired time
period.
1
13
RT. Products were analyzed by H/ C-NMR and GC-MS.
The reaction mixture was allowed to cool down to RT and concentrated
to 50 mL at 40 ˚C by using a rotary evaporator. Demineralized water (150
mL) was added, and the mixture was stirred for 45 min. to hydrolyze the
acetals to the free aldehyde. The aqueous mixture was extracted with
diethyl ether (4x 50 mL). The combined organic layers were then washed
Most crude products consisted of a mixture of the free aldehyde (major
product) and the dimethyl acetal (minor product) due to incomplete
hydrolysis of the aldehyde dimethyl acetals under these workup
conditions. For initial identification the products were separated by
silicagel column chromatography (petroleum ether (8) : ethyl acetate (2))
to give the pure compounds as slightly yellow crystalline solids.
with sat. NaHCO
The organic layer was dried over MgSO4, filtered and concentrated at 40
C under vacuum using a rotary evaporator. The products were purified
by silica gel column chromatography (petroleum ether (8): ethyl acetate
3
and brine until the pH of the water layer was neutral.
˚
Methyl 5-formyl-2-furoate (free aldehyde):
1
13
(
2) and analyzed by H/ C-NMR and GC-MS.
Ethyl 5-formyl-2-furoate (from ethanol as the solvent):
TLC: R value 0.22
TLC: R
f
value 0.19
1
3
H-NMR (400.17 MHz, CDCl ): δ = 9.82 (1 H, s), 7.29-7.26 (2 H, m), 3.96
f
(3 H, s).
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ChemSusChem
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1
H-NMR (400.17 MHz, CDCl
.23 (1H, d, J = 3.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 1.36 (3H, t, J = 7.1 Hz).
3
): δ = 9.77 (1H, s), 7.24 (1H, d, J = 3.8 Hz),
(35 mL water was needed). Remaining particles were removed by
filtration over a micro filter. The clear colorless solution (pH 6) was cooled
in an ice bath and conc. nitric acid (5 mL) was added. A white precipitate
formed immediately in the acidic mixture (pH <1). The precipitate was
collected by filtration, washed with little ice water, followed by washing
with ethanol. The product was dried under vacuum at 40 ˚C to constant
weight, to give 476 mg white product (42 mol% of theory).
7
13
C-NMR (100.62 MHz, CDCl
53.87, 158.08, 179.06.
3
): δ =14.28, 61.96, 118.56, 119.05, 148.04,
1
MS (GC-MS, 70eV): m/z (%) = 168 (22) [M+], 140 (70), 139 (53), 123
20), 95 (35), 67 (7), 39 (38).
(
[46]
Preparation of Au/C catalyst via cationic adsorption
1
H-NMR values correspond to those previously reported by Dawson et
[
42]
Step 1 (cationic adsorption): Activated carbon (SX1G, 10 g) was placed
in a 100 mL beaker and water (40 mL) was added. The suspension was
stirred for 30 min. until the carbon was completely wetted. In a separate
al.
Propyl 5-formyl-2-furoate (from propanol as the solvent):
5
00 mL beaker, tetraammine gold(III)nitrate (334 mg, 0.763mmol) was
-
1
dissolved in 300 mL water (conc. = 2.55mmolL ). Under fast stirring with
an overhead stirrer, the previously prepared carbon suspension was
added to the gold solution as fast as possible. The resulting suspension
was stirred for 2 h at RT. The suspension was filtered over a paper filter,
and the carbon was washed with demineralized water. The carbon with
adsorbed gold was dried under vacuum at 40 ˚C in the presence of
Sicapent.
TLC: R
f
value 0.28
1
3
H-NMR (400.17 MHz, CDCl ): δ = 9.82 (1H, s), 7.29 (1H, d, J = 3.7 Hz),
7.27 (1H, d, J = 3.7 Hz), 4.32 (2H, t, J = 6.8 Hz), 1.88-1.73 (2H, m), 1.02
(3H, t, J = 7.7 Hz).
13
C-NMR (100.62 MHz, CDCl
3
): δ =14.11, 21.91, 67.28, 118.39, 118.79,
147.91, 153.78, 158.03, 178.96.
Step 2 (reduction): A quartz plug-flow reactor was filled with 1.6 g of the
material prepared in step 1. The reactor was flushed with argon, and a
-
1
MS (GC-MS, 70eV): m/z (%) = 182 (3) [M+], 153 (3), 141 (51), 140 (47),
39 (49), 123 (100), 95 (22), 67 (7), 39 (40).
hydrogen flow (8 mLmin ) was applied. The sample was heated to 400
-
1
1
˚C with a ramp of 5 ˚Cmin and was kept at this temperature for 4 h. The
gas flow was switched to argon, and the reactor was allowed to cool to
RT.
Methyl levulinate (from D-fructose and HMF):
The gold loading was determined by elemental analysis (1.3 wt% gold)
and the gold particle size distribution was determined by TEM/HAADF
(average gold particle size 2.2 nm, see supporting information).
TLC: R
f
value 0.50
1
3
H-NMR (400.17 MHz, CDCl ): δ = 3.65 (3H, s), 2.72 (2H, t, J = 6.4 Hz),
2.54 (2H, t, J = 6.4 Hz), 2.18 (3H, s).
[38]
Preparation of dimethyl-FDCA
MS (GC-MS, 70eV): m/z (%) = 130 (2) [M+], 115 (26), 99 (28), 88 (14),
Seventy-five mL Parr MRS5000 pressure reactors were charged with
magnetic stirring bars, substrate (either Me-FFA or Et-FFA, 2 mmol),
methanol (20 mL) and sodium methoxide (43 mg, 0.2 mmol) to give
clear solutions. The 1.3 wt% Au/C catalyst (88 mg, 5.8 µmol Au) was
added, the reactors were closed, flushed 3x with oxygen and then
pressurized at 5 bar. Stirring was started (600 rpm) and the reactions
were allowed to proceed at RT. After 19 h, the reactors were opened and
the reaction mixtures were filtered over a paper filter to remove the
catalyst. Methanol was removed under reduced pressure to give
yellow/brown solids. The remaining sodium methoxide was removed by
taking up the reaction mixtures in chloroform (product dissolves while
NaOMe does not dissolve) followed by filtration over Pasteur pipettes
filled with cotton wool. The clear yellow solutions were concentrated to
give dimethyl-FDCA as slightly yellow crystalline solids (365-368 mg,
71 (10), 58 (15), 55 (26), 43 (100).
1
H-NMR values correspond to those previously reported by Morandi et
[
43]
[44]
al. and GC-MS values correspond to Hengne et al.
Preparation of tetraammine gold(III)nitrate (catalyst precursor)
The following method was adapted from two previously reported
[
45]
procedures:
Ammonium nitrate (95 g, 1.19 mol) was dissolved in 70
mL water in a 300 mL Erlenmeyer flask. The mixture was stirred and
allowed to warm to RT to give a clear solution (pH 4.5). Using a plastic
spoon (Caution: do not use a metal spoon), gold(III)chloride trihydrate (1
g, 2.54 mmol) was added to the solution. The solution changed from
colorless to yellow/orange and the pH dropped to pH 1.3. Under stirring,
conc. ammonia was carefully dropped to the solution until the pH
1
13
yield 99%). The product was analyzed by H/ C-NMR and GC-MS.
[
45a]
increased to pH 5. Although Mason et al.
reported precipitation of the
TLC: R
f
value 0.32
desired product at pH 5, we did not observe any precipitation after 30 min.
The pH was increased to pH 7 by addition of conc. ammonia and a white
1
[
45b]
3
H-NMR (400.17 MHz, CDCl ): δ = 7.22 (2 H, s), 3.94 (6 H, s).
precipitate formed immediately as reported by Skibstead et al.
Caution: care must be taken not to increase the pH too much, since
(
13
[
45a]
C-NMR (100.62 MHz, CDCl ): δ = 52.33, 118.41, 146.64, 158.37.
explosive gold salts might be formed otherwise ) The white suspension
was allowed to stand at 7 ˚C for 16 h, after which the precipitate was
collected by filtration. The residue was washed with a small amount of ice
water, followed by diethyl ether.
3
+
MS (GC-MS, 70eV): m/z (%) = 184 (32) [M ], 153 (100), 139 (1), 125 (6),
113 (1), 95 (8), 82 (2), 69 (6), 59 (9), 53 (4), 38 (9).
[
47]
The product was dried at RT and transported to a 100 mL beaker. Water
was added under stirring until the salt was almost completely dissolved
NMR and MS are in agreement with previously reported values.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201700051
FULL PAPER
[
[
15] S. E. Harding, I. H. Smith, C. J. Lawson, R. J. Gahler, S. Wood,
Carbohydr. Polym. 2011, 83, 329-338.
16] S.-P. Nie, C. Wang, S. W. Cui, Q. Wang, M.-Y. Xie, G. O. Phillips, Food
Hydrocolloids 2013, 32, 221-227.
Acknowledgements
This research is co-financed with TKI-funding from the
Topconsortia for Knowledge & Innovation (TKI’s) of the Ministry
of Economic Affairs in The Netherlands, and the companies
Royal Cosun, RefrescoGerber, Arkema, and North Seaweed.
The authors would like to thank W. Vogelzang, BSc. for fruitful
discussions that led to initiating of this research strategy, Dr. A.E.
Frissen for the NMR and XRD analyses, Alniek van Zeeland,
BSc. for the HPLC-MS analyses, and Hans Meeldijk (Utrecht
University) for TEM/HAADF imaging.
[
[
17] G. A. Adams, Can. J. Chem. 1954, 32, 186-194.
18] a) F. M. Gírio, C. Fonseca, F. Carvalheiro, L. C. Duarte, S. Marques, R.
Bogel-Łukasik, Bioresour. Technol. 2010, 101, 4775-4800; b) R.
Moriana, F. Vilaplana, M. Ek, Cellulose (Dordrecht, Neth.) 2015, 22,
3409-3423.
[19] a) J. Raedts, S. W. M. Kengen, J. van der Oost, Glycoconjugate J.
2011, 28, 57-66; b) A. Haug, B. Larsen, Acta Chem. Scand. 1963, 17,
1653-1662.
[20] a) J. Lu, H. Yang, J. Hao, C. Wu, L. Liu, N. Xu, R. J. Linhardt, Z. Zhang,
Carbohydr. Polym. 2015, 122, 180-188; b) D. I. Sanchez-Machado, J.
Lopez-Cervantes, J. Lopez-Hernandez, P. Paseiro-Losada, J. Simal-
Lozano, Biomed. Chromatogr. 2004, 18, 90-97;
[
21] a) T. T. Nguyen, S. Brown, A. A. Fedorov, E. V. Fedorov, P. C. Babbitt,
S. C. Almo, F. M. Raushel, Biochemistry 2008, 47, 1194-1206; b) T. T.
Nguyen, A. A. Fedorov, L. Williams, E. V. Fedorov, Y. Li, C. Xu, S. C.
Almo, F. M. Raushel, Biochemistry 2009, 48, 8879-8890; c) Y. Takagi,
M. Kanda, Y. Nakata, Biochim. Biophys. Acta 1959, 31, 264-265; d) A.
J. Wahba, J. W. Hickman, G. Ashwell, J. Am. Chem. Soc. 1958, 80,
2594-2595.
Keywords: furandicarboxylic acid • isomerization • levulinic acid
•
oxidation • uronic acids
[
1]
a) E. de Jong, M. A. Dam, L. Sipos, G.-J. M. Gruter, ACS Symp. Ser.
[
[
22] A. D. McNaught, Pure Appl. Chem. 1996, 68, 1919-2008.
23] a) B. Carlsson, Samuelso.O, T. Popoff, O. Theander, Acta Chem.
Scand. 1969, 23, 261-267; b) E. R. Nelson, P. F. Nelson, Aust. J. Chem.
1968, 21, 2323-2325; c) H. S. Prihar, D. S. Feingold, Carbohydr. Res.
1980, 86, 302-304.
24] S. J. Angyal, The Lobry de Bruyn–Alberda van Ekenstein
transformation and related reactions, in: Glycoscience: epimerisation,
isomerisation and rearrangement reactions of carbohydrates, Vol. 215,
Springer-Verlag, Berlin, 2001.
2012, 1105, 1-13; b) R. J. I. Knoop, W. Vogelzang, J. van Haveren, D.
S. van Es, J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 4191-4199; c)
K. Matsuda, H. Horie, K. Ito, Plastic film containing poly(alkylene-2,5-
furandicarboxylate), 2012, US20120258299; d) J. A. Moore, W. W.
Bunting, Polym. Sci. Technol. 1985, 31, 51-91; e) A. F. Sousa, C. Vilela,
A. C. Fonseca, M. Matos, C. S. R. Freire, G.-J. M. Gruter, J. F. J.
Coelho, A. J. D. Silvestre, Polym. Chem. 2015, 6, 5961-5983; f) S.
Thiyagarajan, W. Vogelzang, R. J. I. Knoop, A. E. Frissen, J. van
Haveren, D. S. van Es, Green Chem. 2014, 16, 1957-1966; g) D. S.
Van Es, J. Van Haveren, A. E. Frissen, J. C. Van De Kolk, Improved
stabilized flexible PVC compositions and articles made from flexible
PVC using bio-based plasticizer 2013, WO2013184661; h) M. Vannini,
P. Marchese, A. Celli, C. Lorenzetti, Green Chem. 2015, 17, 4162-
[
[25] F. Ehrlich, R. Guttmann, Ber. Dtsch. Chem. Ges. 1934, 67B, 573-589.
[
26] a) K. Gao, D. Wei, Appl. Microbiol. Biotechnol. 2006, 70, 135-139; b) Z.
Hameršak, N. Pavlović, V. Delić, V. Šunjić, Carbohydr. Res. 1997, 302,
245-249; c) S. Kambourakis, B. M. Griffin, K. V. Martin, Compositions
and methods for producing chemicals and derivatives thereof, 2015,
WO2015143381.
[
[
27] E. Votocek, S. Malachta, Collect. Czech. Chem. Commun. 1934, 6,
241-250.
4166; i) J. Wu, P. Eduard, S. Thiyagarajan, B. A. J. Noordover, D. S.
28] a) E. Stutz, H. Deuel, Helv. Chim Acta 1956, 39, 2126-2130; b) E. Stutz,
H. Deuel, Helv. Chim Acta 1958, 41, 1722-1730.
van Es, C. E. Koning, ChemSusChem 2015, 8, 67-72.
[
[
[
2]
3]
4]
R.-J. van Putten, J. C. van der Waal, E. de Jong, C. B. Rasrendra, H. J.
Heeres, J. G. de Vries, Chem. Rev. 2013, 113, 1499-1597.
D. W. Rackemann, W. O. S. Doherty, Biofuels, Bioprod. Biorefin. 2011,
[29] M. Luisa, D. Ramos, M. Madalena, M. Caldeira, V. M. S. Gil, Carbohydr.
Res. 1996, 286, 1-15.
[30] a) T. H. Emaga, N. Rabetafika, C. S. Blecker, M. Paquot, Biotechnol.,
Agron., Soc. Environ. 2012, 16, 139-147; b) M. C. A. Leitao, M. L. A.
Silva, M. I. N. Januario, H. G. Azinheira, Carbohydr. Polym. 1995, 26,
165-169; c) E. C. Shorey, J. B. Martin, J. Am. Chem. Soc. 1930, 52,
4907-4915.
5, 198-214.
I. van Zandvoort, Y. Wang, C. B. Rasrendra, E. R. H. van Eck, P. C. A.
Bruijnincx, H. J. Heeres, B. M. Weckhuysen, ChemSusChem 2013, 6,
1
745-1758.
A. J. J. E. Eerhart, A. P. C. Faaij, M. K. Patel, Energy Environ. Sci.
012, 5, 6407-6422.
[
[
5]
6]
[31] O. Eyrisch, G. Sinerius, W.-D. Fessner, Carbohydr. Res. 1993, 238,
2
287-306.
G. J. M. Gruter, F. Dautzenberg, Preparation of 5-alkoxymethylfurfural
ethers for use as fuel or monomer in polymerization 2007,
EP1834950A1834951.
a) H.-G. Elias, Macromolecules, Volume 2: Industrial Polymers and
Synthesis, Wiley-VCH, 2007; b) K. A. Weissermel, H.-J. , Industrial
Organic Chemistry, Fourt, Completely Revised Edition, Wiley-VCH,
[32] T. C. Crawford, G. C. Andrews, H. Faubl, G. N. Chmurny, J. Am. Chem.
Soc. 1980, 102, 2220-2225.
[33] C. Chen, H. Yamamoto, T. Kwan, Chem. Pharm. Bull. 1970, 18, 815-
[
7]
8]
9]
819.
[34] a) A. Kosaka, M. Aida, Y. Katsumoto, J. Mol. Struct. 2015, 1093, 195-
200; b) M. Sinnott, Carbohydrate Chemistry and Biochemistry:
Structure and Mechanism, 2nd Edition, RSC Publishing, 2013.
[35] A. A. Rosatella, S. P. Simeonov, R. F. M. Frade, C. A. M. Afonso,
Green Chem. 2011, 13, 754-793.
[36] a) J. B. Binder, A. V. Cefali, J. J. Blank, R. T. Raines, Energy Environ.
Sci. 2010, 3, 765-771; b) R.-J. van Putten, J. N. M. Soetedjo, E. A.
Pidko, J. C. van der Waal, E. J. M. Hensen, E. de Jong, H. J. Heeres,
ChemSusChem 2013, 6, 1681-1687; c) G. Yang, E. A. Pidko, E. J. M.
Hensen, J. Catal. 2012, 295, 122-132.
2003.
[
a) http://faostat.fao.org/site/339/default.aspx; b) A. W. M. Huijbregts, in
1st joint IIRB-ASSBT Congress, San Antonio, Texas, USA, 2003, pp.
451-459; c) A. Oosterveld, G. Beldman, H. A. Schols, Carbohydr. Res.
1996, 288, 143-153.
[
[
U. S. Ramasamy, H. Gruppen, H. A. Schols, J. Agric. Food Chem.
013, 61, 6077-6085.
2
10] a) J. Kuivanen, H. Dantas, D. Mojzita, P. Richard, E. Mallmann, A. Biz,
N. Krieger, D. Mitchell, AMB Express 2014, 4, 33; b) A. M. Torrado, S.
Cortes, J. M. Salgado, B. Max, N. Rodriguez, B. P. Bibbins, A. Converti,
J. M. Dominguez, Braz. J. Microbiol. 2011, 42, 394-409.
11] K. Rommi, J. Rahikainen, J. Vartiainen, U. Holopainen, P. Lahtinen, K.
Honkapää, R. Lantto, J. Appl. Polym. Sci. 2016, 133, 42862.
12] L. A. Pfaltzgraff, M. De Bruyn, E. C. Cooper, V. Budarin, J. H. Clark,
Green Chem 2013, 15, 307-314.
13] a) A. F. Belalcazar Otalora, Pectin extraction from coffee pulp 2014,
WO2014083032; b) J. E. Braham, R. Bressani, Coffee Pulp:
Composition, Technology, and Utilization, IDRC, 1979; c) R.
Padmapriya, J. A. Tharian, T. Thirunalasundari, Int. J. Curr. Sci. 2013,
[
37] K. Iffland, J. Sherwood, M. Carus, A. Raschka, T. Farmer, J. Clark,
nova paper #8 on bio-based economy 2015-11 2015, www.bio-
based.eu/nova-papers.
[
[
[
[38] E. Taarning, I. S. Nielsen, K. Egeblad, R. Madsen, C. H. Christensen,
ChemSusChem 2008, 1, 75-78.
[39] a) J. Deng, H.-J. Song, M.-S. Cui, Y.-P. Du, Y. Fu, ChemSusChem
2014, 7, 3334-3340; b) F. Menegazzo, T. Fantinel, M. Signoretto, F.
Pinna, M. Manzoli, J. Catal. 2014, 319, 61-70; c) A. S. Shaikh, K. R.
Parker, L. R. Partin, M. E. Janka, Method for producing purified dialkyl-
furan-2,5-dicarboxylate by physical separation and solid liquid
separation, 2013, WO2013191942.
83-91.
[40] R. I. Khusnutdinov, A. R. Bayguzina, R. R. Mukminov, Russ. Chem.
Bull. 2013, 62, 93-97.
[
14] A. G. M. Leijdekkers, J. P. M. Bink, S. Geutjes, H. A. Schols, H.
Gruppen, Bioresour. Technol. 2013, 128, 518-525.
[
41] S. A. Shackelford, M. B. Anderson, L. C. Christie, T. Goetzen, M. C.
Guzman, M. A. Hananel, W. D. Kornreich, H. Li, V. P. Pathak, A. K.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201700051
FULL PAPER
Rabinovich, R. J. Rajapakse, L. K. Truesdale, S. M. Tsank, H. N. Vazir,
J. Org. Chem. 2003, 68, 267-275.
[46] P. A. Pyryaev, B. L. Moroz, D. A. Zyuzin, A. V. Nartova, V. I.
Bukhtiyarov, Kinet. Catal. 2010, 51, 885-892.
[
[
[
[
42] M. I. Dawson, R. Chan, P. D. Hobbs, W. Chao, L. J. Schiff, J. Med.
Chem. 1983, 26, 1282-1293.
43] B. Morandi, Z. K. Wickens, R. H. Grubbs, Angew. Chem. 2013, 125,
[47] a) S. Thiyagarajan, A. Pukin, J. van Haveren, M. Lutz, D. S. van Es,
RSC Adv. 2013, 3, 15678-15686; b) V. Tsanaktsis, G. Z. Papageorgiou,
D. N. Bikiaris, J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2617-
2632.
[48] B. Matsuhiro, A. B. Zanlungo, G. G. S. Dutton, Carbohydr. Res. 1981,
97, 11-18.
9
933–9936; Angew. Chem., Int. Ed. 2013, 52, 9751-9754.
44] A. M. Hengne, S. B. Kamble, C. V. Rode, Green Chem. 2013, 15,
540-2547.
45] a) W. R. Mason, III, H. B. Gray, J. Am. Chem. Soc. 1968, 90, 5721-
2
[49] F. van der Klis, A. E. Frissen, J. van Haveren, D. S. van Es,
ChemSusChem 2013, 6, 1640-1645.
5729; b) L. H. Skibsted, J. Bjerrum, Acta Chem. Scand., Ser. A 1974,
28, 740-746.
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Synthesis of FDCA-esters without
concomitant levulinic acid formation,
starting from non-food feedstocks.
Furandicarboxylic acid (FDCA) is a promising biobased building block e.g. for the
production of packaging materials. Current routes to FDCA involve the notoriously
unstable HMF as an intermediate, leading to levulinic acid and humin formation.
nd
Here we present a novel route to 2 generation FDCA-esters, starting from readily
available agro residues like sugar beet pulp and citrus pulp. Here, formylfuroic acid
esters are formed as the stable intermediates, blocking pathways to levulinic acid
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