One-Pot Transformation of Carbohydrates into Valuable Furan Derivatives via 5-Hydroxymethylfurfural

Article abstract of DOI:10.1002/cctc.201701106

5-Hydroxymethylfurfural (HMF) is a pivotal chemical in the utilization of biomass as a chemical feedstock. For this approach the vast majority of methods require access to pure HMF from biomass before its utilization, which incorporates one or more purification steps that obstruct industrial implementation. We describe an operationally simple and versatile method that encompasses both the dehydration of several carbohydrate substrates into HMF and subsequently its direct conversion into various high value-added furan derivatives in a one-pot process. To that end, we selected the aldol condensation of HMF with methyl isobutyl ketone (MIBK) as a model reaction. With the optimized conditions of solvent and base catalyst in hand, the one-pot dehydration of fructose and the condensation sequence with various ketones afforded the products in good overall yields over two steps. The scope of the process was expanded to more complex carbohydrates, such as glucose, lactose, sucrose, cellobiose, and inulin. Moreover, by fine-tuning the reaction conditions, the one-pot methodology in which we used inulin as the substrate was highly efficient if applied to various other important reactions, such as oxidation, reduction, and Cannizzaro and Baylis–Hillman reactions, which rendered the corresponding furan derivatives in high overall yields.

Full text of DOI:10.1002/cctc.201701106

Accepted Article
Title: One-Pot Transformation of Carbohydrates into Valuable Furan
Derivatives
Authors: Pauli Wrigstedt, Juha Keskiväli, Jesus Perea-Buceta, and
Timo Juhani Repo
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ChemCatChem
10.1002/cctc.201701106
FULL PAPER
One-Pot Transformation of Carbohydrates into Valuable Furan
Derivatives
[a]
[a]
[a]
[a]
Pauli Wrigstedt, Juha Keskiväli, J. E. Perea-Buceta and Timo Repo*
5
-Hydroxymethylfurfural (HMF) constitutes one of the pivotal
condensation to furnish biofuel precursors.[3] Furthermore, well-
known processes such as the Cannizzaro or the Baylis-Hillman
reaction have been also studied.[4] However, most of these
transformations have been performed using HMF in pure form
rather than producing it directly from hexoses to subsequently
utilize it in a single one-pot reaction.[5] To date, the direct one-pot
transformation of carbohydrates into chemicals through HMF
mostly involve acid-catalyzed etherification (i.e. to produce
ethoxymethylfurfural, EMF), oxidation to FDCA and reduction to
DMF, DMTHF or BHMF.[5] However, these processes typically
utilize fructose as substrate and examples of reactions employing
more complex carbohydrates are rare.[
chemicals to utilize biomass as chemical feedstock. For this approach
the vast majority of methods require accessing to pure HMF from
biomass before its utilization, thus incorporating one or more
purification steps that obstruct industrial implementation. This work
describes an operationally simple and versatile method
encompassing in a one-pot process both the dehydration of several
carbohydrate substrates into HMF and subsequently its direct
conversion into various high value-added furan derivatives. To that
end, we selected the aldol condensation of HMF with methyl isobutyl
ketone (MIBK) as a model reaction. With the optimized conditions of
solvent and base catalyst in hand, the one-pot dehydration of fructose
and condensation sequence with various ketones afforded the
products in good overall yields over two steps. The scope of the
process was successfully expanded to more complex carbohydrates,
such as glucose, lactose, sucrose, cellobiose and inulin. Moreover, by
fine-tuning the reaction conditions, the one-pot methodology using
inulin as substrate was found to be highly efficient when applied to
various other important reaction types, such as oxidation, reduction,
1b, 1d, 5]
Cannizzaro
and
Baylis-Hillman
reactions,
rendering
the
corresponding furan derivatives in high overall yields.
Introduction
Amidst the growing global environmental concerns, there is a
tremendous interest to gradually shift from traditional fossil fuel-
derived feedstocks towards more sustainable and renewable
biomass. In this sense, 5-hydroxymethylfurfural (HMF) has
emerged as one of the main platform chemicals to bridge the
connection between fossil- and biofuel resources. Therefore,
numerous homo- and heterogeneous catalytic systems have
been extensively investigated for its production through
dehydration of carbohydrates.[1]
Scheme 1. HMF as a platform chemical for the production of valuable furanic
compounds.
The relatively high cost of HMF, and problems associated to
its stability and purification,[1b] constitute major challenges for its
Additionally, a number of catalytic routes have been recently
developed to transform HMF into solvents, biofuels, building
blocks for bioplastics and commodity chemicals.[1b, 1d, 2] The most
implementation
in
large-scale
biorefinery
applications.
Additionally, the dehydration of carbohydrates into HMF under
acidic conditions is often accompanied by a series of side
reactions, such as HMF hydrolysis and self-condensation
reactions,[ which decrease the efficiency of the processes. An
interesting alternative to overcome these problems is to convert
notable of these (Scheme 1) encompass the reduction of HMF to
2,5-bis(hydroxylmethyl)furan (BHMF), its oxidation to 2,5-
furandicarboxylic acid (FDCA) or 2,5-diformylfuran (DFF), its
hydrogenation to dimethylfuran (DMF) or dimethyltetrahydrofuran
6]
(
DMTHF), its rehydration to levulinic acid
and its aldol
HMF
to
5-chloromethylfurfural
(CMF)
directly
from
[7]
carbohydrates. Due to the sensitivity of CMF to moisture,
several methods have been developed to convert CMF into stable
products, such as the conversion to 5-acetoxyfurfural,[1b, 8] which,
[
a]
P. Wrigstedt, J. Keskiväli, Dr. J.E. Perea-Buceta, Prof. T. Repo
Department of Chemistry
University of Helsinki
in turn, has been shown to be an amenable platform chemical for
various processes.[9] However, this strategy requires an extra
synthetic step to access the desired end products, and, from a
processing viewpoint, the development of a highly efficient
catalytic systems enabling the one-pot conversion of sugars
directly into the end products would be highly desirable.
P.O. Box 55 (A. I. Virtasen aukio 1)
FI-00014 University of Helsinki, Finland
E-mail: timo.repo@helsinki.fi
Supporting information for this article is given via a link at the end of
the document.
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ChemCatChem
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FULL PAPER
Furthermore, the synthesis of CMF involves drastic conditions
such as the use of large stoichiometric amounts of concentrated
HCl that do not comply with the desirable requirements of
sustainability at large industrial scale.[7b]
exception of using 1 equiv of KBr instead of saturated solution to
avoid phase separation. Even though the dehydration step gave
HMF in lower yields than the biphasic system (71% vs 86%), the
aldol adduct 1 was now obtained in promising 57% yield.
In the context of our current research to valorize biomass as
chemical feedstock,[3c, 10] we describe herein the development of
one-pot transformation of carbohydrates through HMF to various
furan derivatives. Our strategy involved the optimization of the
reaction conditions for fructose using the aldol condensation with
methyl isobutyl ketone (MIBK) as model system, after which the
methodology was successfully implemented to more complex
carbohydrate substrates as well as to various reaction types, such
as reduction, oxidation, Cannizzaro and Baylis-Hillman reactions.
Scheme 2. Initial conditions for the one-pot two-step conversion of fructose to
HMF-MIBK aldol adduct 1.
Results and discussion
Optimization of the fructose dehydration step
At this stage, we adopted a strategy to optimize separately
Initial experiments
the fructose dehydration step, using an aqueous H
dioxane monophasic system. First, we investigated in more detail
the effect of KBr and H SO on the fructose dehydration step. The
screening of the added amount of KBr (10, 20, 30, 50 and 100
mol-%) and H SO (0.017M = 4.5 mol%, 0.035 M = 9 mol% and
.07 M = 18 mol%) identified 30 mol-% of KBr and 0.017 M H SO
as the optimal combination, affording HMF in 84% yield with
quantitative conversion of fructose in 1 min at 150 C under MW
2 4
SO -KBr-
To date, a plethora of homo- and heterogeneous catalytic
methods for the generation of HMF from fructose have been
reported.[1] We began our investigation to develop a sequential
2
4
one-pot fructose dehydration and aldol condensation
2
4
0
2
4
methodology by selecting
microwave-enhanced biphasic (KBr+HCl)aq-MeCN system
Scheme 2, i).[10b] Alkalimetal halide salts, such as NaCl, KBr or
a
practical and high-yielding
̊
(
heating. The use of higher than 50 mol-% of KBr led to a small
decrease in HMF yield, indicating that KBr also enhances the
HMF decomposition. Nevertheless, the optimization studies
revealed the remarkable catalytic effect of KBr on the reaction in
KCl, serve a dual role in this type of biphasic systems. First, their
use as saturated solutions ensures the continuous extraction of
HMF to the organic phase during the reaction.[11] This limits the
formation of water-promoted byproducts, such as levulinic acid
and humins,[6a] and results in higher HMF yields and
the presence of H SO . The fructose conversion and HMF yields,
2
4
selectivities.[12] Moreover, alkalimetal halides catalyze the
obtained with or without the presence of KBr, together with the
initial fructose consumption and HMF formation rates are
illustrated in Figure 1. As expected, without the presence of KBr,
the initial rates for both fructose consumption and HMF yields
increased by increasing the acid concentration gradually from
dehydration of fructose in both aqueous and organic media.[10a, 13]
This positive catalytic effect on the HMF yields has been attributed
to the anions rather than cations in solution and is reported to
decrease in the order Br > I > Cl in organic solvents,[13b] and Br >
Cl > I in aqueous biphasic systems.[10a]
2 4
0.017 M to 0.07 M. In comparison to 0.017 M H SO only case,
the addition of 30 mol-% of KBr accelerated the initial fructose
consumption rate by twofold. The drastic catalytic influence of KBr
on the reaction was manifested in the HMF formation rate, which
soared to 16-fold compared to the reaction without KBr (0.017 M
For the second step, we applied typical aldol condensation
conditions (Scheme 2). First the reaction media was basified with
NaOH, after which the condensation partner MIBK was added and
the resulting biphasic mixture heated at 60
these conditions, the first dehydration step gave HMF in very good
6% yield, but low HMF conversion (25%) and aldol adduct 1 yield
12%) were obtained in the second step. The low conversion was
̊C for 5 hours. Under
H
2
SO
initial HMF formation rate was observed in comparison to the
reaction with the highest acid concentration of 0.07 M H SO . As
the initial reaction rates of fructose consumption and HMF
formation with KBr+0.017 M H SO are closer to each other (0.30
vs 0.223 M/s, 1.3-fold) compared to 0.017 M H SO only (0.14 vs.
.014 M/s, tenfold), it is obvious that KBr greatly enhance the
4 2 4
vs 0.017 M H SO + KBr). Even a threefold increase in the
8
(
2
4
ascribed to the biphasic system, in which the reagents were
heterogeneously distributed in immiscible phases, consequently
preventing the deprotonation of MIBK by NaOH at an appropriate
rate. This assumption was supported by the fact that water
miscible acetone reacts readily with HMF under similar
2
4
2
4
0
fructose dehydration by accelerating the conversion of
intermediate products to HMF. Despite our attempts, we were not
able to detect any intermediates by HPLC analysis, indicating that
they are unstable (short-lived) under the applied conditions.
conditions.[ We addressed this by switching from a biphasic to
3b]
2 4
a monophasic reaction setup applying aq. H SO -KBr-organic
solvent system (Scheme 2, ii).[14] 1,4-dioxane was chosen as
model co-solvent due to its water miscibility (small amount of
water is essential for dissolving fructose) and compatibility
towards slightly basic and acidic conditions. The combined
dehydration and condensation reaction was performed under the
same conditions as with the biphasic system (Scheme 2), with the
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ChemCatChem
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FULL PAPER
elimination with water as base to form the 1,2-enol, which then
rapidly undergoes two β-elimination to form HMF. The plausible
explanation for the superior performance of bromides over
chlorides and iodides is that bromide is more suitable leaving
group (appropriate stability) to promote the β-elimination over the
oxocarbenium formation of the 2-halo-fructofuranose, which leads
to the crucial 1,2-enol intermediate.
Scheme 3. The catalytic routes i and ii proposed to occur in organic solvents
after the initial dehydration of C-2 (reference 13c). In aqueous solutions route i
-
can be ruled out as H
2
O (excess) is significantly more basic than Br (30 mol-%).
Once the optimized amounts of KBr and
established (0.017 M H SO ~5 mol-%, 30 mol-% KBr), we
screened a series of green (γ-valerolactone, EtOH, i-PrOH)
2 4
H SO were
2
4
[20]
and water miscible (THF, EtOH, i-PrOH, dioxane, MeCN and
DMF) solvents for the fructose dehydration step (Figure 2). High-
performing DMSO[21] and ionic liquid solvents[1a] were excluded
Figure 1. Impact of KBr in the fructose dehydration step in the presence of
from this study due to the incompatibility of DMSO towards the
applied conditions[22] and relatively expensive and operationally
H
2
SO
mg fructose, 30 mol-% KBr in H
20 s.
4
. Fructose conversion (above) and HMF yield (below). Conditions: 150
2
SO (aq)-dioxane (0.3-2.1 mL), MW 150 C, 1-
4
̊
tricky ionic liquids. In addition to 1,4-dioxane, high HMF yields
were obtained in MeCN (82%) and i-PrOH (80%), albeit longer
reaction time was required with the latter as a result of slower
fructose conversion rates. The reactions in those solvents were
highly selective, resulting in only low levels of by-products, such
as levulinic acid, formic acid and insoluble polymeric products
1
From a mechanistic point of view, the catalytic effect of halides
is not fully established, particularly in aqueous solutions.
According to our results above, the catalytic amplification
promoted by bromides (or any other halide) occurs after the initial
(
visible humins), often formed concurrently with HMF.[1b]
) catalysed dehydration at C-2 in fructose,[1b,
Conversely, poor HMF selectivity was observed using EtOH,
presumably due to the competitive formation of 5-
ethoxymethylfurfural under acidic conditions.[23] Surprisingly,
other polar aprotic solvents such as DMF, γ-valerolactone (GVL)
or THF were ineffective, giving HMF in very low yields and
selectivities. These results imply that those solvents suppress the
Brønsted acid (H SO
2 4
1
5]
forming a highly reactive fructofuranosyl oxocarbenium ion
step 1, Scheme 3). This ion can spontaneously deprotonate at
(
[15]
C-1 to form an 1,2-enol (step 2), which then doubly dehydrates,
driven by aromatization, to form HMF (step 3).[16] In organic
solvents, it was proposed that halides can catalyze the reaction
following two possible mechanisms; they act either as a base or
a nucleophile, thus facilitating the formation of the 1,2-enol (routes
i and ii, Scheme 3).[13c] In our aqueous system, however, the role
H
2
SO
exceptionally high yields of glucose obtained in cellobiose and
biomass hydrolysis using the H SO -GVL system in place of
SO
-dioxane.[24] It is worth noting that, in comparison to MW
4
-catalyzed fructose dehydration. This may explain the
2
4
H
2
4
of bromide as base (route i) can be ruled out by the fact that water
+
irradiation, the conversion rates of fructose in 1,4-dioxane, MeCN
or i-PrOH under conventional heating were considerably slower
and resulted in substantially lower HMF yields of 81%, 72% and
is significantly more basic (pKa of H
3
O = -1.7) than bromide (pKa
of HBr = -8.8).[
17]
Additionally, the fructofuranosyl oxocarbenium
ion is known to be attacked readily by alcohols[18] and fluorides.[19]
52%, respectively (see Table S2 in Supporting Information).
Consequently, it is evident that in aqueous solutions the dramatic
catalytic influence of halides originates from their nucleophilic
attack to the C-2 of the fructofuranosyl oxocarbenium ion (route ii,
Scheme 3). The formed 2-halo-fructofuranose then experiences
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Figure 3. In situ 1H NMR spectra for the aldol condensation of HMF with MIBK
Figure 2. The effect of solvents in the dehydration of fructose to HMF.
Conditions: 150 mg fructose, 30 mol% KBr in 0.125 M H
mL), MW 150 C, 120 s. *Reaction time 180 s.
2
SO
4
-solvent (0.3-2.1
in CD
(30% NaOD), 0.6 mL CD
to 3 h, 55 C. Initial spectrum recorded before the addition of NaOD.
3
CN-D
2
O-NaOD. Conditions: 15 mg HMF, 21 µL MIBK (2 equiv), 5 µL
̊
3
CN, 0.07 mL D O, 1 mg K SO4 and 2 mg KBr, 20 min
2
2
̊
One-pot dehydration and aldol condensation sequence
using fructose
With the range of suitable solvents (1,4-dioxane, MeCN and i-
PrOH) and general conditions of the monophasic fructose
dehydration and aldol condensation steps in hand, we next
explored the effect of various bases, including NaOH, KOH,
To gain detailed insight into the aldol condensation of HMF
1
with MIBK, we followed the progress of the reaction by H NMR
K
2
CO
3
, Cs
2
CO
3
, piperidine and tert-BuOK, and various Lewis
, Fe(NO , Eu(OTf) or InCl
, [3a, 26] on the
spectroscopy, utilizing commercial HMF with NaOD as a base and
acids, such as MgAlO
4
3
)
3
3
3
a mixture of CD
conditions used in the first step, equivalent amounts of K
from H SO ) and KBr were added to the reaction. As Figure 3
3
CN-D
2
O as solvent. To simulate the reaction
aldol condensation step using MIBK as a model condensation
partner. The reactions were conducted in one-pot fashion, in
which the reaction time of the first step depended on the solvent
2
SO
4
(
2
4
illustrates, the reaction proceeded rather cleanly and virtually full
conversion was achieved after 3 h. Further experimentation
showed that maintaining the reaction temperature in the range of
(
Table 1). In accordance with previous report,[3c] a strong base
was required for the deprotonation of MIBK, regardless of the
applied solvent. Thus, only NaOH, KOH and t-BuOK were
applicable to the reaction, each of them producing 1 in similar
yields ranging from 68-70% (in 1,4-dioxane). No reaction
occurred using weaker bases or Lewis acids, even at higher
40 to 65 ̊C had no notable effect on products yields, albeit the
reaction was accelerated at higher temperature, which is a
common feature in aldol condensation reactions. However, lower
product yields were recorded at temperatures higher than 65 ̊C.
1
13
temperature (110 ̊C ) or with extended reaction time (15 h).
The H and C NMR spectra, measured after simple extraction of
Curiously, the used solvent did not affect the outcome of the aldol
condensation, since the differences observed in 1 yields were
related to the obtained yields of HMF with different solvents in the
first reaction step (Figure 2). Additionally, using higher amount of
base or MIBK did not further increase the 1 yield, which, in turn,
was only improved by 3% using commercial HMF (entry 1 vs entry
the reaction mixture with EtOAc, showed no presence of organic
impurities in the crude products (See crude 1H and 13C NMR
spectra of 1 in Supporting Information). It is well-known that
Cannizzaro reactions can take place under the applied
conditions,[25] resulting in HMF disproportionation to give
equimolar amounts of 5-(hydroxymethyl)furan-2-carboxylic acid
4, Table 1). Pleasingly, other ketones such as 2-butanone and
(
HMFCA) and 2,5-bis(hydroxylmethyl)furan (BHMF), the former
acetone were successfully subjected to the reaction sequence
giving the corresponding aldol adducts in 59% (2:1 mixture of
isomers, i.e.,1- or 3-aldol addition adducts) and 51% yield,
respectively.
of which is soluble in basic water and thus, not detectable on the
crude 1H and 13C NMR spectra (extraction with EtOAc). However,
the HPLC analysis of the control reaction conducted in the
absence of MIBK (commercial HMF and 50 mol% NaOH in H
2
O-
MeCN, 3 h at 55 C), found only traces of HMFCA present in the
̊
aqueous phase after extraction, thus confirming that the
Cannizzaro reaction under such mildly basic conditions was
negligible.
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FULL PAPER
amount of base for the second step when CrCl
3 2
×6H O was
Table 1. Influence of different bases and solvents on the aldol condensation
step.[a]
[
29]
utilized (CrCl ×6H O forms acidic solutions in water, pH ~ 2)
3
2
.
From the results shown on Figure 4, all of the carbohydrates
tested were compatible with the reaction conditions and gave the
HMF-MIBK condensation product 1. The reaction performed
notably well with fructan inulin in all the applicable solvents and
afforded 1 in close to equal yield to that obtained from fructose.
Additionally, the high HMF yield obtained from inulin (75-78%
depending on solvent) is comparable to those obtained in ionic
Yield [e]
Ketone [b]
Base [c]
Organic solvent [d]
Entry
(
%)
70[f]
1
2
3
4
5
9
MIBK
MIBK
NaOH
NaOH
NaOH
NaOH
KOH
1,4-dioxane
MeCN
liquids[ and aqueous biphasic systems.
yield of 37% was recorded using sucrose as substrate in the
absence of an isomerization catalyst. The addition of CrCl ×6H
30]
[31]
However, a low 1
68
67
73[g]
68
70
61
59
51
-
3
2
O
MIBK
i-PrOH
catalyst improved the 1 yield up to 52% due to the enhanced
glucose-to-fructose isomerization. The system was less effective
in terms of 1 yield when glucose or glucose-containing lactose or
cellobiose were utilized as substrates, giving 1 in 41%, 30% and
MIBK
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
i-PrOH
MIBK
4
1% yields respectively. Clearly, this was linked to the first
reaction step, which gave HMF in lower yields than the reactions
2
starting from fructose. However, the presence of CrCl ×6H O
MIBK
t-BuOK
NaOH
NaOH
NaOH
NaOH
10
11
11
12
2-butanone
2-butanone
Acetone
Acetophenone
3
during the aldol condensation step had no significant effect on the
reaction outcome and only a slight loss of approximately 5% in 1
selectivity was observed (comparison of HMF and 1 yields with or
without catalyst), thus underscoring the robustness of the aldol
condensation step. Appreciably, the reaction could be scaled up
to gram-scale using inulin as substrate (from 0.83 mmol to 6.7
mmol, eightfold) with only a small decrease in the 1 yield from
65% to 60%, albeit a slightly longer reaction time for both steps (5
min, 4 h) was required.
1,4-dioxane
1,4-dioxane
[
a] Conditions: 0.83 mmol fructose, 10 mol% CrCl
KBr in 0.125 M H SO -dioxane (0.3 mL-2.1 mL); [b] 2.4 mmol of ketone; [c]
0 mol% of base; [d] Reaction times in the first step; 60 s with 1,4-dioxane,
20 s with MeCN and 180 sec with i-PrOH; [e] Overall yield over two steps
3 2
×6H O if used, 30 mol%
2
4
5
1
determined by GC-FID; [f] isolated yield of 58% after column chromatography;
g] Commercial HMF.
[
Table 2. One-pot transformation of various carbohydrates to 1.[a]
Dehydration and aldol condensation sequence using other
carbohydrates
HMF Yield
1 Yield
(%)[c]
Most of the direct one-pot carbohydrate transformations to
chemicals through HMF employ fructose as substrate and reports
dealing with the compatibility of these processes with more
complex carbohydrates are rare.[5] Therefore, we aimed to extend
the one-pot dehydration-condensation process to glucose,
lactose, cellobiose, sucrose and inulin. It is well-known that the
synthesis of HMF from glucose or other glucose-containing
Entry
Carbohydrate
Solvent
(
%)[b]
78
75
75
55
45
67
56
39
74
1
2
Inulin
Inulin
1,4-dioxane
MeCN
65
62
63
41
37
52
41
30
60
3
Inulin
i-PrOH
carbohydrates (sucrose, lactose and cellobiose) requires
a
4
Glucose + Cr(III)
Sucrose
i-PrOH
catalyst that is able to isomerize glucose to fructose (aldose-to-
ketose isomerization) during the reaction.[27] Several
5
i-PrOH
homogeneous Lewis acid catalysts, such as SnCl
AlCl ×6H O and CrCl ×6H
O,[1a, 1b] have been identified to
efficiently catalyze this transformation, out of which CrCl ×6H
has been shown to perform best under aqueous conditions.
Therefore, we employed CrCl ×6H O on the trials where glucose
4
×5H
2
O,
6
Sucrose + Cr(III)
Cellobiose + Cr(III)
Lactose + Cr(III)
Inulin
i-PrOH
3
2
3
2
7
i-PrOH
3
2
O
[
10]
8
i-PrOH
3
2
9[d]
1,4-dioxane
was present (the reaction was optimized using glucose as a
model compound; see Table S4 in Supporting Information). It is
worth noting that, unlike Cr , which is highly toxic, CrIII is very
stable and essential for the normal metabolism of carbohydrates,
lipids, and fats in humans.[28] The reactions were conducted using
VI
3 2
[a] Conditions: 0.83 mmol carbohydrate, 10 mol% CrCl ×6H O if used, 30
mol-% KBr in 0.125 M H SO -dioxane (0.3 mL-2.1 mL), reaction times in the
2 4
first step; 4 min with 1,4-dioxane and 5 min with MeCN and i-PrOH; [b]
Determined by HPLC; [c] Determined by GC-FID and correspond to the
the KBr-H
2
SO
4
-i-PrOH system and MIBK as ketone partner.
overall yields over two steps [d] 1.2 g inulin, 30 mol-% KBr in 0.25 M H
dioxane (1.2 mL-8.0 mL), MW 150 C, 5 min.
2 4
SO -
However, we slightly modified the reaction conditions by using
extended reaction times for the first dehydration step and a larger
̊
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One-pot transformation of inulin into furan-based chemicals
suggesting that the reaction decelerates significantly by
increasing the water content (dilution of NaOH concentration). In
addition to the Cannizzaro reaction, the one-pot inulin dehydration
The presence of alcohol and aldehyde functional groups in
HMF makes it a versatile platform chemical for the syntheses of a
variety of bio-based value-added products, as shown in Scheme
4
and reduction sequence using NaBH in i-PrOH as co-solvent
gave BHMF in a good overall yield of 67% (Scheme 5).
1. As these transformations have been mostly performed using
pure HMF rather than produced directly from hexoses in a single
one-pot reaction,[5] we next asked whether the one-pot
dehydration and functionalization sequence described herein
might be applicable to other transformations than aldol
condensation, using inulin as substrate. Accordingly, the
compatibility of various reaction types for the direct one-pot
conversion of inulin to furan derivatives were investigated,
including the selective oxidation of HMF using Pt/C[32] and
One-pot inulin dehydration and Baylis-Hillman reaction sequence.
The Baylis–Hillman reaction is one of the most important C-
C bond-forming processes in modern organic synthesis.[38] This
process involves reacting an aldehyde with an activated alkene in
the presence of a tertiary amine base to give a densely
functionalized product. The reaction exhibits a highly favorable
atom economical character as every atom present in the
substrates is found in the products. Furthermore, the Baylis–
Hillman reaction is compatible with HMF in aqueous media,[4]
which increases its attractiveness from the point of view of
sustainable chemistry.[39] As an example, the Baylis-Hillman
adducts of HMF could be utilized for the manufacture of bio-based
acrylate thermoplastics.[40]
Ru/C,[33] the reduction of HMF to BHMF by NaBH
Hillman coupling of HMF with methyl acrylate[4a] and the
,[9] the Baylis-
4
[25]
Cannizzaro reaction. An overview of these reactions is depicted
in Scheme 5.
One-pot inulin dehydration and Cannizzaro reaction sequence.
Table 4. One-pot inulin dehydration and subsequent Baylis-Hillman reaction
with methyl acrylate.[a]
The Cannizzaro reaction is
a
base-induced redox
disproportionation of non-enolizable aldehydes to carboxylic
acids and alcohols. When applied to HMF, the Cannizzaro
reaction yields an equimolar mixture of BHMF and HMFCA, both
of which are equally important biobased chemicals. BHMF find
[34]
applications in the manufacture of polyurethane foams, crown
ethers[35] and polyesters,[1b] while HMFCA serves as a component
for novel bioplastics, such as polyesters,[36] and as precursor to
prepare 2,5-furandicarboxylic acid.
Relative yields (%)[c]
2 yield
(%)[d]
Entry
Solvent
Base[b]
2
HMF
100
100
80
1
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
i-PrOH
DBU
-
n.d.
n.d.
n.d.
58
Table 3. One-pot inulin dehydration and subsequent Cannizzaro reaction.[a]
DBN
-
3
DMAP
DABCO
DABCO
DABCO
DABCO
20
91
77
49
96
4
9
BHMF (%)[b]
HMFCA (%) [c]
5
23
48
Solvent
i-PrOH
NaOH
4 M (aq)
Powder
Powder
Powder
Y
Y
Y
HMF (%)
6
MeCN
51
32
21
30
30
29
20
31
30
30
8
1
1
3
7[e]
1,4-dioxane
4
60
i-PrOH
MeCN
[a] Conditions: 0.83 mmol inulin, 30 mol-% KBr in 0.125 M H
0.3 mL-2.1 mL), reaction times in the first step; 3 min with 1,4-dioxane and 5
min with MeCN and i-PrOH; [b] 2 equiv of base; [c] Determined by H NMR
from the crude products; [d] isolated yield after column chromatography; [e]
2 4
SO -dioxane
(
1
,4-dioxane
1
24 h reaction time
[
a] Conditions: 0.83 mmol inulin, 30 mol-% KBr in 0.125 M H
2 4
SO -dioxane
(
0.3 mL-2.1 mL), MW 150 C, reaction times in the first step; 3 min with 1,4-
̊
dioxane and 5 min with MeCN and i-PrOH; 4 equiv of NaOH; [b] BHMF
purified according to Ref. 25 [c] Yields determined by HPLC and correspond
to the overall yields over two steps.
The integrated inulin dehydration and Baylis-Hillman
reaction of HMF with methyl acrylate was studied in different
conditions of solvent and base catalyst and the results are
detailed in Table 4. Of the catalysts studied, only DABCO (1,4-
Diazabicyclo[2.2.2]octane) was found to be compatible with the
applied conditions (2 equiv of DABCO and 3 equiv of methyl
acrylate, r.t., 16 hours)[41]. With other tertiary amines, such as
The treatment of HMF with NaOH (4 equiv) in 1,4-dioxane,
using our one-pot protocol starting from inulin (Table 3), afforded
both BHMF and HMFCA in good overall yields of 30% and 31%,
respectively. The combined product yields corresponds to 81%
yield from HMF (Inulin to HMF in 75% yield, see Table 2), which
are comparable to those obtained from pure HMF.[25, 37] Likewise
with aldol condensation, the reaction proceeded well regardless
of the solvent used. However, better yields were obtained when
NaOH was added as a powder instead of as a 4 M solution, a fact
DBN
(1,5-Diazabicyclo[4.3.0]non-5-ene)
or
DBU
(1,8-
Diazabicyclo[5.4.0]undec-7-ene),[
38a, 42]
no Baylis-Hillman adduct
was formed, while the reaction occurred using DMAP (4-
dimethylaminopyridine),[43] but extremely sluggishly. Even with
DABCO, the reaction was found to proceed quite slowly, as is
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ChemCatChem
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often observed for Baylis-Hillman reactions. Conversely to
Cannizzaro and aldol condensation reactions, the rate of the
Baylis-Hillman reaction was affected by the used organic co-
solvent (relative yields of 2 and HMF in Table 4). In terms of
and HMF rehydration and cross-polymerization, which are known
to occur at elevated temperatures under strongly alkaline
conditions.[55] In all cases, intermediate products 5-
hydroxymethylfuranoic acid (HMFCA) and 5-formylfuran
carboxylic acid (FFCA) were detected after the reaction, the
distribution of which depended on the base or solvent employed
reaction rate the binary solvent system 1,4-dioxane/H
2
O
performed better than i-PrOH/H O or MeCN/H O, and afforded
2
2
the Baylis-Hillman adduct 2 in a good yield of 58% over two steps,
which was raised up to 60% by increasing the reaction time to 24
(see Table S5 in Supporting Information). With NaHCO
the main product of the reaction was FDCA, accompanied by
HMFCA and small amounts of FFCA, while with Na CO and
3
as base
h. However, heating the reaction (50
̊
2
3
product yield and selectivity.
NaOH the major products were FFCA and HMFCA, respectively.
The presence of those intermediates suggested that the reaction
did not go to completion after 10 hours of reaction time. However,
with all bases, the extension of the reaction time up to 20 h had
only marginal effect on the product distribution, which indicates
that the Pt/C catalyst deactivation occurs in a relatively early stage
One-pot inulin dehydration and oxidation to FDCA by Pt/C.
,5-furandicarboxylic acid (FDCA) has been identified as
2
one of the most promising building blocks for the production of
value-added chemicals derived from biomass.[44] Recently, FDCA
has evolved as a promising renewable substitute for petroleum-
derived terephthalic acid, which is used in the manufacture of
polyethylene terephthalate (PET) and polybutyleneterephthalate
of the reaction. Gratifyingly, with NaHCO
3
as base, the
evaporation of the organic co-solvent (MeCN)[
56]
before the
second oxidation step leveraged the FDCA yield from 52% to 70%
(94% yield if calculated from HMF) with full conversion of HMF
and, HMFCA and FFCA intermediates. The same result was
achieved by isolating the crude HMF after the first dehydration
step by extraction and evaporation of solvents, followed by
(
PBT) plastics,[45] or as a precursor to adipic acid, one of the two
monomers used in nylon 6,6.[46] The preferred route for the
production of FDCA involves the catalytic transformation of
biomass-derived carbohydrates to HMF, followed by catalytic
oxidation (Scheme 4).[47] Various systems using Pt-,[32a] Pd-,[48]
Ru[49] or Au-based[50] heterogeneous catalysts have been
reported to catalyze the oxidation of pure HMF to FDCA in nearly
quantitative yields under neutral (mainly Au)[50a] or basic aqueous
conditions. Direct synthetic routes to FDCA from fructose, that
combine a dehydration and oxidation steps in one-pot, have been
reported using Pt−Bi/C in combination with solid acid,[51]
3
oxidation using Pt/C in NaHCO . This demonstrated that, with
respect to pure water, the presence of an organic co-solvent
significantly hampered the reaction. This negative impact was
attributed to either strong adsorption of the formed FDCA salt or
other intermediates to the platinum surface (salts less soluble in
the organic solvents)[32b, 57] or coordination of the organic co-
solvent to the platinum center, resulting in the deceleration of the
reaction and the premature deactivation of the Pt/C catalyst.
[
52]
Co(acac)−SiO2 as bifunctional catalyst and Pt/C with NaOH in
i-PrOH[53] resulting in FCDA yields of 25%, 71% and 51%,
respectively. To the best of our knowledge, no literature reports
exist which describe the direct one-pot transformation of inulin to
FDCA. In our studies, the second HMF oxidation step was
performed using Pt/C as oxidation catalyst due to its well-known
versatility and efficiency.[1b, 32b, 48, 54] The effect of various bases,
Table 5. One-pot inulin dehydration to HMF and subsequent oxidation to
2,5-furandicarboxylic acid.
Entry
Solvent
1,4-dioxane
MeCN
Base
NaOH
NaOH
C
HMF(%)[b]
98
Y
FDCA (%)[c]
such as NaOH, Na
2
CO
3
and NaHCO
3
, on the oxidation outcome
was simultaneously investigated using either 1,4-dioxane or
MeCN as the organic co-solvent (Table 5).
1
2
3
4
5
6
7
8
21
25
2
99
1,4-dioxane
MeCN
Na
2
2
CO
CO
3
3
54
Na
58
4
1,4-dioxane
MeCN
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
97
41
52
70
71
96
MeCN[d]
>99
>99
Scheme 4. HMF oxidation routes to FDCA and intermediates.
Water[e]
The screen of base and co-solvent identified NaHCO
MeCN as the best combination which afforded FCDA in 52% yield
10 hours at 70 C, Table 5). The application of stronger bases, i.e.
NaOH or Na CO , under the same conditions rendered lower
FDCA yields and selectivities (carbon balance) regardless of the
organic co-solvent. This can be partly explained by HMF
degradation and side reactions, such as the Cannizzaro reaction
3
and
[
a] Conditions: 0.83 mmol inulin, 30 mol% KBr, 0.3 mL 0.0125 M H
solvent (0.3 mL-2.1 mL); reaction time 3 min with dioxane and 4 min with
MeCN; p(O )= 8 bar, 2.5 mol% Pt/C, 3 equiv of base; [b] HMF conversion
determined byHPLC; [c] overall yields over two steps, determined by HPLC;
d] Performed in one-pot by evaporating MeCN before the second step; [e]
Performed in NaHCO solution using crude HMF, isolated after the first step
by extraction and evaporation of solvents.
2 4
SO -
2
(
̊
2
3
[
3
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ChemCatChem
10.1002/cctc.201701106
FULL PAPER
Unfortunately, recycling of the Pt/C catalyst by filtering and
washing with water after the reaction resulted in decrease in the
FDCA yields to 21% and 9% after the second and third run,
respectively (see detailed product distribution on Figure S2 in
Supporting Information). Thus, regeneration of the activity of Pt/C
catalyst after the reaction still remains a challenge.
between 7 and 8, while at pH lower than 6 or higher than 8 the
reaction was very slow. Similar behavior was observed previously
in the aqueous oxidation of HMF to DFF or FDCA by Ru on
various supports,[58] whereas the addition of hydrotalcite provided
appropriate basicity (pH = 8-10) improving conversions and
product yields.[63] At slightly basic conditions (pH 7-8) the reaction
was highly selective affording FFCA in good 56% overall yield
over two steps, accompanied by 12% yield of FDCA and full
conversion of HMF. Shortening the reaction time from 14 to 10
hours increased the FFCA yield to 61% due to the diminished
exposure time to oxidation. As expected, increase in the reaction
One-pot inulin dehydration and oxidation to furan derivatives by
Ru/C.
Ru-based heterogenous catalysts on various supports have
been reported to catalyze the oxidation of HMF selectively to DFF,
FFCA or FDCA in organic solvents[33, 58] or water[49, 58-59] under
neutral or basic conditions. In parallel to our studies on the direct
one-pot inulin transformation to FDCA by Pt/C, we performed
similar experiments using Ru/C as an oxidation catalyst, in the
temperature from 80
rate and leveraged the FDCA yield to 44%.
̊C to 140 ̊C accelerated the FFCA oxidation
[49, 59]
These results
emphasize the utility of Ru/C as a convenient catalyst for the
oxidation of HMF, as the products distribution can be tuned, even
with crude HMF, by simply adjusting the reaction conditions, such
as initial pH, temperature and reaction time.
presence of NaHCO
and co-workers, who showed that Ru on hydrotalcite can be used
in the one-pot synthesis of DFF from fructose[60] and raffinose[61]
3
(Table 6). Inspired by the work of Ebitani
,
we aimed to optimize our one-pot inulin transformation process to
DFF, which is a valuable bio-based precursor for pharmaceuticals,
furanic biopolymers, antifungal agents and furan-urea resins.[62]
However, shortly after beginning our studies it turned out that the
presence of water, which is essential to our system, caused
overoxidation to FFCA (Scheme 4),[33] resulting in a mixture of
DFF, FFCA and FDCA (2nd step: 5 mol% Ru/C, 3 equiv NaHCO
3
,
80 ̊
C, 14 h, 1,4-dioxane as co-solvent). Attempts to overcome this
problem by altering temperature, organic co-solvent (MeCN) or
the initial pH of the reaction failed and relatively low yields of DFF
were obtained (maximum 25%, entry 4, Table 6).
Table 6. One-pot inulin dehydration to HMF and subsequent oxidation by
Ru/C.[a]
Entry
pH[b]
8-9
7-8
6-7
5-6
<3
C
HMF (%)
65
Y
FDCA (%)
Y
FFCA (%)
Y
DFF (%)
1[c]
Scheme 5. Overview of the direct one pot two-step transformations of inulin
through HMF into value-added products conducted in this study. Applicable
solvents on bold. Yields are overall yields over two steps and the yields of the
second step on brackets (calculated from HMF). * MeCN was evaporated before
the second step.
trace
34
12
-
2
3
>99
>99
58
14
8
56
43
20
25
8
4
3
18
5[d]
Conclusions
15
-
3
6[e]
7[f]
7-8
7-8
>99
>99
7
61
-
This work illustrates that the carbohydrate dehydration to
HMF and its further derivatization by a one-pot reaction strategy
is a powerful approach to generate value-added furan derivatives.
We have demonstrated that HMF in crude form, obtained in
sufficient purity by using straightforward microwave-enhanced
aqueous dehydration of various carbohydrates, is amenable to
various transformations, such as the base-catalyzed aldol
condensation with ketones and the Cannizzaro and Baylis-
Hillman reactions as well as the oxidation by Pt/C or Ru/C and
44
22
-
[
a] Conditions: 0.83 mmol inulin, 30 mol% KBr, 0.3 mL 0.0125 M H
dioxane (0.3 mL-2.1 mL; p(O )= 8 bar, 2.5 mol% Ru/C; yields corresponds
to the overall yields over two steps (HPLC); [b] Initial pH, adjusted with
NaHCO ; [c] Sat. aq. NaHCO was used [d] without addition of NaHCO ; [e]
Reaction time 8 h [f] 3 h 140 C
2 4
SO -
2
3
3
3
In spite of the setback in the selective formation of DFF,
those studies unveiled the significant impact of the initial reaction
pH on the Ru/C activity and the reaction outcome. In terms of
Ru/C activity, the optimal initial pH range was found to be narrow
4
reduction by NaBH , in a single one-pot reaction. Most strikingly,
fructose-containing inulin, which is preferred over fructose in the
synthesis of HMF due to its non-digestible nature, was found to
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ChemCatChem
10.1002/cctc.201701106
FULL PAPER
be compatible with all the reaction types investigated, and
provided the respective furan derivatives in very good yields. This
was especially manifested in the one-pot oxidation of inulin to 2,5-
furandicarboxylic acid with Pt/C as catalyst, which proceeded in
very good 70% overall yield over two steps (94% if calculated from
HMF). In terms of product yields, the major limitation of the
process was the first dehydration step since the second step,
regardless of the reaction type, proceeded in very similar yields
compared to those of reported for pure HMF in similar reaction
conditions. In this sense, the efficiency of the process could be
improved simply by improving the carbohydrate dehydration step.
This could be achieved by optimizing the reaction conditions for
other solvent systems, such as ionic liquids or purely organic
media, which are known to be efficient in carbohydrate
dehydration to HMF. Collectively the results presented in this
study highlight the potential of transforming carbohydrates to high
value-added furan derivatives in a one-pot manner without
resorting to purification of HMF intermediate, thus bridging the
gap between the large scale exploitation of biomass and the
sustainable production of commodity chemical and fuels.
Procedure for the one-pot fructose dehydration and aldol
condensation sequence (Figures 2 and 3 and Table 1)
To a 2-5 ml microwave vial with a magnetic stirring bar containing fructose
(0.15g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30 mol %)
was added 0.3 mL of 0.125 M H2SO4. After dissolution of fructose, 2.1 mL
of the organic solvent (1.4-dioxane, MeCN, i-PrOH, γ-valerolactone, DMF,
THF or EtOH) was added, the vial was closed with aluminum/silicone crimp
cap and the solution was heated at 150 °C in the microwave reactor
(Biotage Initiator). After required time (2 min, except with 1,4-dioxane 1
min and with i-PrOH 3 min), the vial was immediately cooled down to room
temperature, whereupon 0.4 mL of 1 M NaOH (0.4 mmol) and 0.30 mL of
methyl isobutyl ketone, 0.18 mL of acetone or 0.21 mL of 2-butanone (2.4
mmol) were added and the solution was heated at 55 °C for three hours
under oil bath. Then, EtOAc (25 mL) and brine (10 mL) were added, the
organic layer separated and dried over Na2SO4. The product yield was
determined from this solution by GC-FID (diluted to 50 mL) using
acetophenone as an internal standard. Additionally, in the case of fructose
in 1,4-dioxane, after evaporation of the solvents, the purification by column
chromatography afforded HMF-MIBK adduct 1 (EtOAc:CHCl3 1:4, Rf = 0.5,
colorless oil) in 58% yield, HMF-2-butanone adduct (EtOAc:hexane 1:1, Rf
=
0.25, light green oil) in 61% yield as a mixture of two isomers (2:1 ratio,
1H NMR) and HMF-acetone adduct (EtOAc:hexane 1.5:1, Rf = 0.30,
colorless oil) in 51% yield. 1-(5-(hydroxymethyl)furan-2-yl)-5-methylhex-1-
1
en-3-one (1); H NMR (300 MHz, chloroform-d) δ 0.95 (s, 3H), 0.97 (s, 3H),
Experimental Section
1.98 (br. s, 1H), 2.09-2.32 (m, 1H), 2.46 (d, J = 7.0 Hz, 2H), 4.65 (s, 2H),
.38 (d, J = 3.3 Hz, 1H), 6.60 (d, J = 3.4 Hz, 1H), 6.64 (d, J = 15.9 Hz, 1H),
6
General
7.28 (d, J = 15.8 Hz, 1H). 13C NMR (75 MHz, chloroform-d) δ 22.8, 25.5,
50.8, 57.8, 110.6, 116.6, 123.8, 128.5, 151.2, 156.7, 200.0. HMF-2-
butanone adducts: Major isomer 1-(5-(hydroxymethyl)furan-2-yl)pent-1-
en-3-one: H NMR (300 MHz, chloroform-d) δ 1.12 (t, J = 7.3 Hz, 3H), 2.50
All solvents, bases, carbohydrates, Pt/C, Ru/C and CrCl3×6H2O were
purchased from commercial sources and used without further purification
unless otherwise noted. All the reactions were carried out in 2–5 mL glass
vials using a Biotage Initiator microwave reactor (2.45 GHz magnetron).
The instrument uses one IR sensor to measure temperature of the reaction
mixture and adjusts the heating power accordingly. The absorption level
was set to “very high” and the reaction mixture was stirred with magnetic
stirring at 600 rpm.
1
(
6
br. s, 1H), 2.60 (q, J = 7.3 Hz, 2H), 4.64 (s, 2H), 6.36 (d, J = 3.2 Hz, 1H),
.58 (d, J = 3.3 Hz), 6.62 (d, J = 16.0 Hz, 1H), 7.26 (d, J = 15.9 Hz, 1H);
13C NMR (75 MHz, chloroform-d) δ 8.4, 34.7, 57.7, 110.5, 116.6, 123.1,
1
3
2
28.5, 151.1, 156.9, 200.8. Minor isomer 4-(5-(hydroxymethyl)furan-2-yl)-
-methylbut-3-en-2-one: H NMR (300 MHz, chloroform-d) δ 2.10 (s, 3H),
.38 (s, 3H), 2.50 (br, 1H), 4.62 (s, 2H), 6.43 (d, J = 3.4 Hz, 1H), 6.63 (d,
J = 3.4 Hz, 1H), 7.25 (s, 1H); 13C NMR (75 MHz, chloroform-d) δ 13.0,
1
2
5.6, 57.7, 110.4, 116.3, 126.9, 134.2, 151.7, 156.3, 199.5. HMF-acetone
HMF, DFF, HMFCA, FFCA and FDCA, glucose and fructose yields were
determined with High Pressure Liquid Chromatography (HPLC). HPLC
runs were performed using Agilent 1200 HPLC system equipped with a
Phenomenex Rezex ROA (300×7.8 mm) column. Sulfuric acid (0.25 mM)
1
adduct: 4-(5-(hydroxymethyl)furan-2-yl)but-3-en-2-one; H NMR (300 MHz,
chloroform-d) δ 2.30 (S, 3H), 2.48 (br. s, 1H), 4.63 (s, 2H), 6.38 (d, J = 3.4
Hz, 1H), 6.56-6.62 (m, 2H), 7.22 (d, J = 15.7 Hz, 1H). 13C NMR (75 MHz,
chloroform-d) 13C NMR (75 MHz, chloroform-d) δ 28.1, 57.7, 110.5, 116.8,
-
1
in water was used as an eluent at 40 ̊C with a flow rate 0.35 mL min . HMF,
124.2, 129.5, 150.8, 157.2, 198.1.
DFF, HMFCA, FFCA and FDCA were detected using UV-detector,
whereas fructose and glucose were analyzed using refractive index (RID)
detector. The exact yields were calculated from calibration curves
prepared for all the compounds from commercially available reagents. The
yields of the aldol condensation product 1 were determined by a gas
chromatograph equipped with a flame ionization detector (GC-FID). The
GC-FID runs were performed using Agilent Technologies 6890N Network
GC System fitted with Agilent HP-INNOWAX column (length 30 m, internal
diameter 0.25 mm and stationary phase thickness 0.25 µm). The
calibration curves were plotted using standard samples with different
concentrations of pure 1 (column chromatography, EtOAc: CHCl3 1:4, Rf =
Procedure for the one-pot glucose, cellobiose, lactose or sucrose
dehydration and aldol condensation with MIBK (Table 2)
To a 2-5 ml microwave vial with a magnetic stirring bar containing the
desired carbohydrate (0.83 mmol), potassium bromide (30 mg, 0.25 mmol,
30 mol%) and CrCl3×6H2O (22.4 mg, 10 mol%) was added 0.3 mL of 0.125
M H2SO4. Then, 2.1 mL of desired organic solvent (1.4-dioxane, MeCN or
i-PrOH,) was added, the vial was closed with aluminum/silicone crimp cap
and the solution was heated at 150 °C in the microwave reactor. After
required time (4 min with 1,4-dioxane, 5 min with MeCN and i-PrOH), the
vial was immediately cooled down to room temperature, whereupon 1.0
mL of 1 M NaOH (1 mmol) and 0.3 mL of methyl isobutyl ketone were
added and the solution was heated at 55 °C for three hours under oil bath.
Then, EtOAc (25 mL) and brine (10 mL) were added, the organic layer
separated and dried over Na2SO4. The product yields were determined
from this solution by GC-FID (diluted to 50 mL).
0
.50). 1H NMR and 13C NMR spectra were acquired at 27 °C using 300
MHz (300 MHz 1H-frequency and 75 MHz 13C-frequency) spectrometer.
Chemical shifts are reported in ppm, and the ppm scale was referenced to
residual solvent peaks (CHCl3 in CDCl3; 7.26 ppm for 1H and 77.16 ppm
for 13C, acetone in acetone-d6; 2.05 ppm for 1H and 29.84 ppm for 13C).
1
3
Coupling constants are reported in Hz. C NMR experiments were
performed using APT pulse sequence (13C { H} proton decoupling).
1
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Procedure for the one-pot inulin dehydration and aldol condensation
with MIBK (Table 2)
Procedure for the one-pot inulin dehydration and Baylis-Hillman
reaction sequence (Table 4)
To a 2-5 ml microwave vial with a magnetic stirring bar containing inulin
To a 2-5 ml microwave vial with a magnetic stirring bar containing inulin
(0.136 g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30
mol-%) was added 0.3 mL solution of 0.125 M H2SO4. The mixture was
stirred for 1 min, whereupon 2.1 mL of the desired solvent (i-PrOH, 1,4-
dioxane or MeCN) was added, the vial closed with aluminum/silicone crimp
cap and the mixture was heated at 150 °C (3 min with 1.4-dioxane, 4 min
with MeCN and 5 min with i-PrOH) in the microwave reactor. Then, the vial
was immediately cooled down to room temperature followed by the
addition of required amount (1.67 mmol, 2 equiv) of base (DABCO, DBN,
DBU or DMAP) and methyl acrylate (0.23 mL, 2.5 mmol). The reaction
mixture was stirred at room temperature for either 16 h or 24 h, whereupon,
EtOAc (20 mL), brine (10 mL) and water (4 mL) were added, the organic
layer was separated and the aqueous layer was further extracted with
EtOAc (3×10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and evaporated to dryness. Purification by column
chromatography (EtOAc:hexane 2:1, Rf = 0.3) in the case of 1,4-dioxane
as solvent and DABCO as a base (24 hours) gave the product as
colourless oil in 60% yield (101 mg, 0.51 mmol). Methyl 2-(hydroxy(5-
(0.136 g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30 mol%)
was added 0.3 mL of 0.125 M H2SO4. The mixture was stirred for 1 min,
whereupon 2.1 mL of the desired organic solvent (1.4-dioxane, MeCN or
i-PrOH) was added, the vial closed with aluminum/silicone crimp cap and
the mixture was heated at 150 °C (3 min with 1.4-dioxane, 4 min with
MeCN and 5 min with i-PrOH) in the microwave reactor. After the required
time, the vial was immediately cooled down to room temperature,
whereupon 0.4 mL of 1 M NaOH and 0.3 mL of methyl isobutyl ketone
were added and the solution was heated at 55 °C for three hours under oil
bath. Then, EtOAc (25 mL) and brine (10 mL) were added, the organic
layer separated and dried over Na2SO4. The product yields in different
solvents were determined from this solution by GC-FID (diluted to 50 mL).
Procedure for the one-pot inulin dehydration and Cannizzaro
reaction sequence (Table 3)
To a 2-5 ml microwave vial with a magnetic stirring bar containing inulin
(
hydroxymethyl)furan-2-yl)methyl)acrylate:
chloroform-d) δ 1.90 (br. s, 1H) 3.17 (br. s, 1H), 3.77 (s, 3H), 4.57 (s, 2H),
.57 (br. s, 1H), 5.97 (q, J = 1.1 Hz, 1H), 6.19 (d, J = 3.2 Hz, 1H), 6.23 (d,
1H
NMR
(300
MHz,
(0.136g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30 mol %)
was added 0.3 mL of 0.125 M H2SO4. The mixture was stirred for 1 min,
whereupon 2.1 mL of the desired organic solvent (1.4-dioxane, MeCN or
i-PrOH) was added, the vial closed with aluminum/silicone crimp cap and
the mixture was heated at 150 °C (3 min with 1.4-dioxane, 4 min with
MeCN and 5 min with i-PrOH) in the microwave reactor. After the required
time, the vial was immediately cooled down to room temperature,
whereupon 133 mg powdered NaOH (3.3 mmol, 4 equiv) was added and
the mixture was stirred at r.t. for 16 hours. Then, 1 M NaOH (10 mL) and
5
J = 3.2 Hz, 1H), 6.39 (q, J = 0.8 Hz, 1H). 13C NMR (75 MHz, chloroform-d)
δ 52.2, 57.4, 67.0, 67.2, 108.1, 108.7, 127.0, 139.5, 154.1, 154.3, 166.6.
Procedure for the one-pot inulin dehydration and oxidation to FDCA
by Pt/C (Table 5)
1
5 mL of EtOAc were added. The organic layer was separated and the
To a 2-5 ml microwave vial with a magnetic stirring bar containing inulin
(0.136 g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30
mol-%) was added 0.3 mL solution of 0.125 M H2SO4. The mixture was
stirred for 1 min, whereupon 2.1 mL of the desired solvent (1,4-dioxane or
MeCN) was added, the vial closed with aluminum/silicone crimp cap and
the mixture was heated at 150 °C (3 min with 1.4-dioxane or 4 min with
MeCN) in the microwave reactor (Biotage Initiator). Then, the vial was
immediately cooled down to room temperature followed by the addition of
3.0 mL of aqueous base solution (2.4 mmol, NaHCO3, Na2CO3 or NaOH)
and 80 mg of 5%-Pt/C (2.5 mol%).* The vial was closed using a septa with
an oxygen inlet (a needle through the septa) and loaded into the reactor
which was closed and pressurised with p=8 bar oxygen, after purging three
aqueous layer was further extracted with EtOAc (3×10 mL). The combined
organic layers were dried over anhydrous Na2SO4 and evaporated to
dryness to give a dark color solid, which was washed with Et2O/hexane to
afford pure 2,5-furandimethanol (BHMF) as a light yellow solid in 30%
yield.[25] The hydroxymethylfuranoic acid (HMFCA) yield (31%) was
determined from the basic aqueous layer (diluted to 50 mL by water) by
1
HPLC analysis. Data for furan-2,5-diyldimethanol (BHMF): H NMR (300
MHz, acetone-d6) δ 4.08 (br. s, 2H), 4.47 (s, 4H), 6.18 (s, 2H). 13C NMR
(75 MHz, acetone-d6) δ 57.2, 108.2, 155.8.
Procedure for the one-pot inulin dehydration and reduction to BHMF
by NaBH4 (Scheme 5).
times to remove air. The reaction mixture was heated at 70 ̊C for 10 h,
whereupon the reactor was cooled to room temperature followed by the
addition of 10 mL of 1 M NaOH and stirring for 3 min. The catalyst was
filtered off and water was added to make the total volume of 50 mL. The
yields of HMF, DFF, HMFCA, FFCA and FDCA were determined from this
solution by HPLC analysis.
To a 2-5 ml microwave vial with a magnetic stirring bar containing inulin
(0.136 g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30
mol-%) was added 0.3 mL solution of 0.125 M H2SO4. The mixture was
stirred for 1 min, whereupon 2.1 mL of i-PrOH was added, the vial closed
with aluminum/silicone crimp cap and the mixture was heated at 150 °C
for 5 min in the microwave reactor (Biotage Initiator). Then, the vial was
immediately cooled down to room temperature followed by the addition of
sodium borohydride in small portions (38 mg, 1.0 mmol). The reaction
mixture was stirred at room temperature for 30 min, whereupon the
solution was neutralized by a careful addition of 0.5 M H2SO4. Then, EtOAc
*
The best FDCA yield was obtained when MeCN was evaporated before
the second step by air flow. Thus, after addition of 2.0 mL of
sat.aq.NaHCO3 (~3 equiv) two phases emerged and MeCN was
evaporated from the top by airflow under stirring.
(
20 mL) and brine (10 mL) were added, the organic layer was separated
Procedure for the one-pot inulin dehydration and oxidation with Ru/C
(Table 6)
and the aqueous layer was further extracted with EtOAc (3×10 mL). The
combined organic layers were dried with anhydrous Na2SO4 and
evaporated to dryness to afford crude product, which was purified by
column chromatography (EtOAc:CHCl3 1:1) to give BHMF as white solid
in 67% yield (68 mg, 0.53 mmol). The H and 13C NMR data of the product
are in accordance with the NMR data of BHMF obtained from Cannizzaro
reaction.
To a 2-5 ml microwave vial with a magnetic stirring bar containing inulin
(0.136 g, 0.83 mmol) and potassium bromide (30 mg, 0.25 mmol, 30
1
mol-%) was added 0.3 mL solution of 0.125 M H2SO4. The mixture was
stirred for 1 min, whereupon 2.1 mL of the desired solvent (1,4-dioxane or
MeCN) was added, the vial closed with aluminum/silicone crimp cap and
the mixture was heated at 150 °C (3 min with 1.4-dioxane or 4 min with
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ChemCatChem
10.1002/cctc.201701106
FULL PAPER
MeCN) in the microwave reactor. Then, the vial was immediately cooled
down to room temperature followed by the addition of required amount of
NaHCO3 to reach the desired initial pH value (dropwise addition of 5%.
NaHCO3; see Table 6) and 42 mg of 5% Ru/C (2.5 mol%). The vial was
closed using a septa with an oxygen inlet (a needle through the septa) and
loaded into the reactor which was closed and pressurised with p=8 bar
oxygen, after purging three times to remove air. The reaction mixture was
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6), whereupon the reactor was cooled to room temperature followed by the
addition of 10 mL of 2 M NaOH and stirring for 3 min. The catalyst was
filtered off and water was added to make the total volume of 50 mL. The
HMF, DFF, HMFCA, FFCA and FDCA yields were determined from this
solution by HPLC analysis as described above.
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Acknowledgements Text.
Keywords: 5-hydroxymethylfurfural • Biomass • Renewable
Resources • Sustainable Chemistry • Carbohydrates
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carbohydrates are converted into high
value-added furan compounds in one-
pot without the need of isolating the
HMF intermediate.
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