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DOI: 10.1002/cssc.201403182
A short literature screening will reveal dozens of research Scheme 2. Mechanism of the photooxygenation of 5-HMF and subsequent
papers which describe hundreds of operational conditions, op- ring opening to HKPA.
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. ing that both compounds have been described in the litera-
Despite these difficulties, and thanks to intensive process opti- ture as being accessible from 5-HMF and singlet oxygen in
mization, the industrial scale production of 5-HMF is slowly only low yields and selectivities.[5] To date, the synthesis of bu-
taking off. Pilot plants with annual production volumes of sev- 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
[a] Dr. T. S. A. Heugebaert, Prof. Dr. C. O. Kappe
form and reported conversions were moderate (72 % and 48 %,
Institute of Chemistry
University of Graz respectively).
Heinrichstrasse 28, 8010 Graz (Austria) In this communication we describe for the first time the
E-mail: oliver.kappe@uni-graz.at preparation of the potential new platform molecule H2MF 6 in
[b] Prof. Dr. C. V. Stevens pure form and its conversion to the polyester precursor 5-hy-
Department of Sustainable Organic Chemistry and Technology
droxy-4-keto-pentenoic acid (10). This was made possible by
GhentUniversity
Coupure Links 653, 9000 Ghent (Belgium) applying continuous flow singlet-oxygen photochemistry,[8, 9]
Supporting Information for this article is available on the WWW under which allows the intensification of singlet-oxygen oxidation of
http://dx.doi.org/10.1002/cssc.201403182. 5-HMF under scalable and safe operation conditions.
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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-
[g]
17 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
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 0000, 00, 1 – 4 &2&
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T. S. A. Heugebaert, C. V. Stevens,
C. O. Kappe*
&& – &&
Singlet-Oxygen Oxidation of 5-
Hydroxymethylfurfural in Continuous
Flow
Rosy future: The selective, high yield- The resulting butenolide (H2MF) is
ing, singlet-oxygen-mediated oxidation shown to be a valuable bio-based poly-
of 5-hydroxymethylfurfural (5-HMF) is ester precursor and the procedure
performed in continuous-flow mode proved to be scalable and applicable to
using rose Bengal as photosensitizer. related bio-based furfurals.
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 0000, 00, 1 – 4 &5&
These are not the final page numbers! ÞÞ