DOI: 10.1002/cssc.
201403182 Communications
Singlet-Oxygen Oxidation of 5-Hydroxymethylfurfural in
Continuous Flow
Thomas S. A. Heugebaert,[a] Christian V. Stevens,[b] and C. Oliver Kappe*[a]
Singlet-oxygen oxidation of 5-hydroxymethylfurfural (5-HMF)
was performed in continuous flow mode using rose Bengal as
photosensitizer. The resulting butenolide (H2MF) was formed
selectively in high yield. The procedure proved to be scalable
and applicable to related bio-based furfurals. Furthermore, pre-
liminary data show that H2MF can be readily isomerized ther-
mally to 5-hydroxy-4-keto-pentenoic acid oligomers.
Over the past decades, 5-hydroxymethylfurfural (5-HMF, 1,
Scheme 1) has gained an almost mythical status as bio-based
building block. It is fully renewable, being manufactured in
high yields from carbohydrate containing materials, using little
more than a suitable solvent and (acidic) catalyst. However, the
road to the commercial production of 5-HMF, and a 5-HMF-
based value chain for that matter, has been paved with difficul-
ties.
Scheme 1. 5-Hydroxymethyl furfural (1) and analogues derived thereof.
A short literature screening will reveal dozens of research
papers which describe hundreds of operational conditions, op-
timizing the isolated yield of 5-HMF.[1] The compound is inher-
ently unstable under both acidic and basic conditions, is sensi-
tive to Cannizaro reaction, to oxidation and polymerization.
Despite these difficulties, and thanks to intensive process opti-
mization, the industrial scale production of 5-HMF is slowly
taking off. Pilot plants with annual production volumes of sev-
[a] Dr. T. S. A. Heugebaert, Prof. Dr. C. O. Kappe
Institute of Chemistry
University of Graz
Heinrichstrasse 28, 8010 Graz (Austria)
E-mail: oliver.kappe@uni-graz.at
[b] Prof. Dr. C. V. Stevens
Department of Sustainable Organic Chemistry and Technology
GhentUniversity
Coupure Links 653, 9000 Ghent (Belgium)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201403182.
This publication is part of a Special Issue on “Green Chemistry and the
Environment”. To view the complete issue, visit:
http://onlinelibrary.wiley.com/doi/10.1002/cssc.v8.10/issuetoc
ChemSusChem 2015, 8, 1648 – 1651
eral tons (5-HMF or directly derived products) are currently
being constructed.[2]
Much like ethylene, 5-HMF serves to very little purpose in
our everyday life and it has now been rightfully labelled as
a platform molecule. It is efficiently manufactured as an indus-
trial intermediate, but must be converted to practically useful
compounds. Among the most promising examples are the bio-
fuel 2,5-dimethylfuran (2),[3] and the polyester precursors 2,5-
furandicarboxylic acid (3) and 2,5-dihydroxymethylfuran (4).[4]
Both dimethylfuran and furan dicarboxylic acid are close to
commercialization.[2]
As 5-HMF-derived compounds, 5-hydroxy-5-(hydroxymethyl)-
furan-2(5 H)-one (H2MF, 6), and the corresponding ring-opened
5-hydroxy-4-keto-pentenoic acid (HKPA, 10) have been postu-
lated as potential expansions of the HMF-platform on several
occasions.[1] In principle these densely functionalized synthetic
scaffolds are directly accessible from 5-HMF by means of sin-
glet-oxygen oxidation (Scheme 2). It is therefore quite surpris-
Scheme 2. Mechanism of the photooxygenation of 5-HMF and subsequent
ring opening to HKPA.
ing that both compounds have been described in the litera-
ture as being accessible from 5-HMF and singlet oxygen in
only low yields and selectivities.[5] To date, the synthesis of bu-
tenolide 6 from 5-HMF has been reported by the Cottier
group on two occasions, providing an acetal mixture (6 along
with 7),[6] that of HKPA (10) has been described only once.[7]
Neither of both compounds has so far been prepared in pure
form and reported conversions were moderate (72 % and 48 %,
respectively).
In this communication we describe for the first time the
preparation of the potential new platform molecule H2MF 6 in
pure form and its conversion to the polyester precursor 5-hy-
droxy-4-keto-pentenoic acid (10). This was made possible by
applying continuous flow singlet-oxygen photochemistry,[8, 9]
which allows the intensification of singlet-oxygen oxidation of
5-HMF under scalable and safe operation conditions.
1648 Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Communications
As a starting point in our investigations towards the contin- tively. In each case, lower substrate concentrations resulted in
uous flow synthesis of butenolide 6, we adapted the 1986 higher conversions. As expected, increasing the oxygen pres-
batch 5-HMF photooxygenation protocol by Cottier and co- sure increased the conversion rate due to higher amounts of
workers[6] to a continuous flow process, applying a reactor set- dissolved oxygen. The pressure could be successfully raised to
up closely related to recent singlet-oxygen flow photochemis- 17 bar. During this process, the flow regime gradually changed
try described by the Seeberger group.[10] The resulting set-up from segmented flow to a homogeneous system, and an in-
is shown in Figure 1 and consists of a 5 mL, 1 mm ID PFA coil, crease of the residence time to 16 min was observed.[11]
In a further attempt to in-
crease the conversion at 0.5 m 5-
HMF, the effect of the oxygen
flow rate was examined using
1.25, 2.5, and 5 equiv of molecu-
lar oxygen. Quite unexpectedly
however, conversions dropped
(entries 11–13). The increased
oxygen flow rates destabilized
the back pressure regulator, re-
Figure 1. Schematic representation of the photoreactor (MFC = mass flow controller, BPR = back pressure regula- sulting in fluctuating flow re-
tor). gimes, depressurization and
short residence times. Therefore,
all further optimizations were
wrapped around a glass cylinder in which a cooled 60 W com- performed using a 0.2 m concentration of 5-HMF and 2.5 equiv
pact fluorescent light source (4000 lumen, 4000 K, cool white) of oxygen. Decreasing both liquid and gas flow rates to 0.15
was placed. The coil was connected to a syringe pump and an and 1.62 mLN min¢1 (the minimum that could be handled re-
oxygen gas bottle by means of a standard T-piece. The gas producibly) resulted in 85 % conversion, at a residence time of
flow was controlled by a mass flow controller (MFC). Initial ex- 27 min (entry 14). Eventually, an increase of the coil volume
periments at 5.1 bar of back pressure showed that a liquid from 5 mL to 10 mL proved to be essential to reach full con-
flow rate of 0.25 mL min¢1, combined with a gas flow rate of version (entry 16).
2.7 mLN min¢1 resulted in a constant segmented flow regime, As shown in Table 1, complete conversion of 5-HMF could
with residence times of approximately 10 min. be obtained using MeOH as solvent. However, in all cases ap-
Initially the effect of oxygen pressure was evaluated, using proximately 12 % of the undesired methyl acetal 7 was formed
substrate concentrations of 0.1, 0.2, and 0.5 m in MeOH during the reaction.[6] To avoid the formation of this side prod-
(Table 1, entries 1–10). These substrate concentrations corre- uct, a solvent screen was initiated (Table 2).
spond to 5, 2.5, and 1 equiv of available oxygen gas, respec- As expected, moving from methanol to the bulkier ethanol
and isopropanol, acetal forma-
tion was suppressed (entries 1–
Table 1. Optimization of the oxidation of 5-HMF to H MF 6. 2 3). The use of water, while elimi-
nating the possibility of acetal
Entry P HMF conc O2 flow rate O2 Observed residence Flow regime Product Conversion formation is plagued with some
[bar] [M][a] [mLN min¢1] [equiv] time [min] ratio 7:6 [%][b]
specific difficulties. Mechanisti-
1 5.1 0.1 2.7 5 10 segmented 13:87 54 cally, it releases formic acid from
2 5.1 0.2 2.7 2.5 10 segmented 14:86 49 5-HMF, which induces acidifica-
3 5.1 0.5 2.7 1 10 segmented 11:89 39
4 6.9 0.1 2.7 5 10 segmented 13:87 78 tion of the reaction medium, re-
5 6.9 0.2 2.7 2.5 10 segmented 9:91 67 sulting in color- and efficiency
6 6.9 0.5 2.7 1 12 near homoge- 7:93 57 loss of the rose Bengal photoca-
neous talyst. A control experiment
7 17.2 0.1 2.7 5 15 homogeneous 14:86 76
8 17.2 0.2 2.7 2.5 16 homogeneous 13:87 73 using methylene blue however
9 17.2 0.5 2.7 1 16 homogeneous 10:90 65 (entry 5), showed this effect to
10[c] 34 0.1 2.7 5 N/A N/A N/A N/A be of marginal importance. The
11 17.2 0.5 3.4 1.25 7 varying 15:85 48 main problem using pure water
12 17.2 0.5 6.8 2.5 5 varying 12:88 38
13 17.2 0.5 13.5 5 4 varying 11:89 27 is the poor solubility of oxygen
14[d] 17.2 0.2 1.62 2.5 27 homogeneous 11:89 85 gas, which results in low conver-
15[d,e] 17.2 0.2 1.62 2.5 27 homogeneous 8:92 100 sions. Therefore, the addition of
16[f] 17.2 0.2 2.7 2.5 42 homogeneous 14:86 100 modifiers was attempted, allevi-
17[g] 17.2 0.2 2.7 2.5 63 homogeneous 14:86 100
ating the low oxygen solubility.
[a] MeOH, 0.25 mL min¢1, rose Bengal 2 mm, 30 8C. [b] Determined by 1H NMR spectroscopy. [c] Reactor failure. While methanol (90 vol %,
[d] Liquid flow rate: 0.15 mL min¢1. [e] T = 100 8C. [f] 10 mL coil. [g] 15 mL coil.
entry 6) was unsuitable, as the

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 Communications

Table 2. Solvent screen for the oxidation of 5-HMF to butenolide 6.[a]

Entry Solvent Photosensitizer Conversion[b] Product ratio

concentration 7:6[b]
1 MeOH 2 mm RB 100 14:86
2 EtOH 2 mm RB 100 7:93
3 iPrOH 1 mm RB[c] 100 3:97
4 H2O 2 mm RB 29 0:100
5 H2O 2 mm MB 34 0:100
6 MeOH/H2O 9/1 1 mm RB[c] 100 18:82
7 Dioxane/H2O 9/1 1 mm RB[c] 100 (99) 0:100 Scheme 3. Substrate scope of the continuous photooxygenation of 5-HMF
8 iPrOH/H2O 1/1 2 mm RB 100 (98) 1:99 and its derivatives.
9[d] iPrOH/H2O 1/1 1 mm RB 100 (98) 1:99

[a] Reactions performed in a 10 mL coil at 0.2 m 5-HMF, 0.25 mL min¢1;

17 bar O2, 2.7 mLN min¢1; residence time 40 min; RB: rose bengal; MB:
methylene blue. [b] Determined by 1H NMR spectroscopy, yields deter-
mined by means of internal standard indicated in parentheses. [c] De-
creased concentration to accommodate lower solubility; [d] Flow rates
were doubled.
acidification of the reaction medium led to increased acetal
formation, both dioxane (90 vol %, entry 7) and iPrOH
(50 vol %, entry 8) delivered butenolide 6 in good selectivity
with full conversion. Both the selectivity and yield (determined
by NMR internal standard) were slightly better using dioxane,
still iPrOH/water was selected for further experiments, given
the fact that dioxane has been identified as environmentally
problematic.[12] Having optimized conversion and selectivity by
means of this solvent switch, we observed that the photosensi-
tizer concentration could be decreased to 1 mm, and that flow
rates of both substrate and molecular oxygen could be dou-
bled without loss of conversion (entry 9).
Using the optimized conditions (0.2 m 5-HMF, 1 mm rose
Bengal, iPrOH/H2O 1/1, 0.5 mL min¢1) a yield of 98 % was ob-
tained (determined by NMR internal standard). In order to
obtain a pure sample column chromatography using EtOAc/
EtOH (98:2 v/v) as the eluent allowed removal of the photoca-
talyst and resulted in an isolated yield of 93 % (97.5 % product
purity, yield based on 85 % purity of commercial 5-HMF, both
were determined by 1H NMR internal standard). The through-
put under these conditions was approx. 0.75 g h¢1 and the re-
actor could be run for 5 h without loss of conversion or selec-
tivity.
The substrate scope of the resulting oxidation is shown in
Scheme 3. The oxidation of 5-acetoxymethylfurfural and 5-
methylfurfural proceeded uneventfully in 81 and 93 % isolated
yield, respectively. Acetal 13 on the other hand could not be
obtained cleanly, and even upon running the reaction in pure
isopropanol to avoid hydrolysis, several degradation products
were visible in the crude. Phthalimide 14 was obtained cleanly
in dioxane/water to ensure substrate solubility and was isolat-
ed in 89 % yield after chromatography. Tertiary amine 15 on
the other hand was found to be unstable, most likely due to
its alkalinity, inducing ring opening of the butenolide (see
below).
While the synthesis of the d-hydroxy-acid HKPA 10 (see
Scheme 2) was previously stated to occur directly from HMF
under photooxygenation conditions, we were not able to
repeat these results.[7] Upon moving to the reported alkaline
aqueous conditions, using methylene blue as sensitizer and
a UV light source (380 nm), 23 % butenolide 6 was formed, and
no HKPA could be observed. We therefore resorted to the iso-
merization of butenolide 6 to HKPA (Scheme 2).
Closely related substrates were reported to display this ring
opening either spontaneously,[13] or upon the addition of pyri-
dine.[10, 14] While the reported 1 mol % delivered little or no con-
version, the addition of 10 mol % pyridine to H2MF led to a con-
version of 33 % after 2 h. Unfortunately, increasing the reaction
time or temperature led only to product degradation. As such,
an elaborate screening of alkaline, acidic, and nucleophilic iso-
merization catalysts was performed (see Supporting Informa-
tion for full data). In two cases full conversion of H2MF was ob-
served. The addition of equimolar amounts of pyridine led to
full conversion to the pyridinium salt of HKPA. However, libera-
tion of the free acid and its subsequent purification proved to
be tedious. We therefore further evaluated the thermal isomer-
ization process in the absence of (reprotoxic) pyridine. Heating
neat H2MF to 70 8C induced full isomerization over 24 h
(Scheme 4). While HPLC, mass spectrometry (MS), and 1H NMR
Scheme 4. Ring opening and subsequent polymerization of H2MF.
analysis indicated a clean conversion to HKPA, internal stand-
ardization showed that the crude product contained only 21 %
(m/m) free HKPA. Much to our delight, high resolution MS anal-
ysis and size exclusion chromatography indicated that HKPA
was formed selectively, and is, in fact, subject to the desired in-
termolecular esterification process at these temperatures. A
mixture of mono-, di-, tri-, and tetramer was obtained and par-
tially fractionated (see the Supporting Information for more de-
tails). It should be noted that the use of crude H2MF delivered
a highly similar oligomeric material. While further characteriza-
tion of these oligomers, and an improved control of the poly-
merization process will eventually be needed, these prelimina-
ry results indicate that H2MF can be used as a polymerization
precursor for bio-based polyesters.

ChemSusChem 2015, 8, 1648 – 1651 www.chemsuschem.org 1650 Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

By utilizing the continuous flow photochemical generation
of singlet oxygen, a scalable, selective and high-yielding syn-
thesis of 5-hydroxy-5-(hydroxymethyl)furan-2(5 H)-one (H2MF)
was described, starting from the fully renewable platform mol-
ecule 5-HMF. The synthetic method proceeds using only light,
oxygen and catalytic amounts of rose Bengal in an environ-
mentally benign iPrOH/H2O solvent mixture. While a quantita-
tive synthesis of the corresponding ring-opened 5-hydroxy-4-
keto-pentenoic acid, HKPA, was not feasible, preliminary results
show that H2MF is an interesting intermediate for the produc-
tion of poly-HKPA, a novel biopolymer.
Experimental Section
The reactor used for oxidation of HMF and its derivatives was con-
structed as shown in the Supporting Information (Figure S1). It
consists of a 10 mL, 1 mm ID PFA coil, wrapped around a glass cyl-
inder in which a cooled 60 W compact fluorescent light source
(4000 lumen, 4000 K, cool white) was placed. The lamp was cooled
by means of a Sunon Maglev 80 Õ 80 Õ 25 mm fan (4.8W, 3200 rpm,
70 m3 h¢1), and the resulting equilibrium temperature of the reac-
tion coil was 35 8C. The coil was connected to a SyrDos syringe
pump, equipped with two 1 mL syringes, and to an oxygen gas
bottle by means of a standard T-piece. The gas flow was controlled
by a mass flow controller (Bronkhorst El-FLOW Select, model F201-
CV-100-ABD-35-T, 0.8–100 mLN min¢1). Reactor pressure was estab-
lished by a standard 17 bar back pressure regulator at the end of
the reactor coil. The reagent and collection vessel were shielded
from ambient light, and the eluting product stream was cooled to
0 8C.
Typical procedure for the oxidation of 5-HMF to 5-hydroxy-5-(hy-
droxymethyl)furan-2(5 H)-one (6, H2MF): 5-Hydroxymethyl-furfural
(85 %, 296 mg, 2 mmol) and Rose Bengal (9 mg, 0.01 mmol) were
diluted in a 1:1 mixture of isopropanol and water, to a total
volume of 10 mL, resulting in final concentrations of 0.2 m and
0.001 m, respectively. The resulting solution was flushed with
Argon, shielded from light and cooled to 0 8C, after which it was
pumped through the photoreactor at 0.5 mL min¢1. Simultaneously,
an O2 gas flow of 5.4 mLN min¢1 was maintained. Collection (0 8C,
dark) was started as soon as the colored solution emerged from
the reactor, approximately 19 min after injection. After removal of
the volatiles, the resulting red oil was submitted to column chro-
matography (98:2 EtOAc/EtOH), delivering pure H2MF (242 mg,
93 %) as a white semi crystalline solid (MP < 40 8C). Note: an un-
identified minor compound with strong UV absorption elutes
closely before the desired product, which in its turn displays poor
UV absorption and some tailing. H (300 MHz, DMSO, TMS): d = 7.56
(s, 1 H, CqOH), 7.40 (d, J = 5.7 Hz, 1 H, C(O)CHCH), 6.25 (d, J = 5.7 Hz,
1 H, C(O)CHCH), 5.19 (s, 1 H, CH2OH), 3.57 ppm (s, 2 H, CH2); C
(75 MHz, DMSO, TMS): d = 171.35 (C(O)), 155.44 (C(O)CHCH), 123.71
(C(O)CHCH), 108.48 (OCqO), 63.91 ppm (OCH2); ñ = 3234 (OH),
1736 cm¢1 (COOR); m/z 129 (M¢H + , 80 %), 259 (2 M¢H + , 100 %);
m/z calcd. for C5H5O3 + , M+ +H + -H2O, 113.02332, Found: 113.02362.
ChemSusChem 2015, 8, 1648 – 1651 www.chemsuschem.org
Communications
Acknowledgements
Financial support for this research from the Fund for Scientific
Research Flanders (FWO Vlaanderen) is gratefully acknowledged.
Keywords: 5-HMF · continuous flow · oxidation ·
photochemistry · singlet oxygen
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Received: October 27, 2014
Published online on December 11, 2014
1651 Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim