Going Beyond the Limits of the Biorenewable Platform: Sodium Dithionite-Promoted Stabilization of 5-Hydroxymethylfurfural

Article abstract of DOI:10.1002/cssc.201800297

The lack of thermal and storage stability and occurrence of side reactions during the processing of 5-hydroxymethylfurfural (5-HMF) limits its potential as biorenewable platform molecule. The addition of small amounts of the readily available sodium dithionite has a remarkable effect on promoting the stability of 5-HMF and inhibiting side reactions, thus helping to circumvent such limitations. The addition of sodium dithionite led to improvements in thermal stability (120 °C, 4 h, neat; 100 % vs. 37 %), under distillation (yield: 85 % vs. 52 %), and in a wide range of reactions, including 5-HMF synthesis under biphasic conditions (yield: 98 % vs. 67 %; purity: 92 % vs. 83 %) and 5-HMF transformations, such as Knoevenagel condensation with Meldrum's acid (yield: 96 % vs. 74 %), Cannizaro reaction (yield: quantitative vs. 83 %), and condensation with primary diamines to give pyridinium salts (yield: 88 % vs. 60 %).

Full text of DOI:10.1002/cssc.201800297

Accepted Article
Title: Going Beyond the Limits of the Biorenewable Platform:
Unprecedented Sodium Dithionite Promoted Stabilization of 5-
Hydroxymethylfurfural
Authors: Carlos Afonso, Rafael Gomes, Yavor N. Mitrev, and Svilen P.
Simeonov
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To be cited as: ChemSusChem 10.1002/cssc.201800297
Link to VoR: http://dx.doi.org/10.1002/cssc.201800297
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10.1002/cssc.201800297
ChemSusChem
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Going Beyond the Limits of the Biorenewable Platform:
Unprecedented Sodium Dithionite Promoted Stabilization
of 5-Hydroxymethylfurfural
Rafael F. A. Gomes,[a] Yavor N. Mitrev,[b] Svilen P. Simeonov,*[a,b] Carlos A. M. Afonso*[a]
Abstract: The lack of thermal and storage stability and
occurrence of side reactions during the processing of 5-
hydroxymethylfurfural (5-HMF) limits its potential as
biorenewable platform molecule. The addition of small
amounts of the readily available sodium dithionite promotes
remarkable effect over the 5-HMF stability and the inhibition
of side reactions thus allowing to circumvent those
limitations. As for instance: (i) thermal stability (120oC, 4 h,
neat; 100% vs 37%); (ii) distillation (yield: 85% vs 52%); (iii)
5-HMF synthesis under biphasic conditions (yield: 98% vs
67%; purity: 92% vs 83%). 5-HMF transformations, such as
(i) Knoevenagel condensation with Meldrum’s acid (yield:
96% vs 74%); (ii) Cannizaro reaction (yield: quantitative vs
83%); (iii) condensation with primary diamines to pyridinium
salts (yield: 88% vs 60%).
limits the production and purification by distillation due to
thermal and storage/transportation instability and general
occurrence of side reactions, such as the formation of
humins2 and dimerization to the corresponding ether3 5,5′-
oxy(bis-methylene)-2-furaldehyde (OBMF).
As described by numerous authors,2a,4 during our ongoing
studies on the production5 and utilization6 of 5-HMF we were
commonly facing problems caused by the unstable nature of
this compound. Typically, the reactions were accompanied
with the formation of large amounts of black tarry materials
leading to low yields and difficult purifications, thus limiting to
a large extend the potential of the 5-HMF platform. In
addition, according to the idea of green chemistry and
“biorefinery concept” the utilization of all carbon atoms of the
resource is a major goal, thus the occurrence of side
reactions, which limits the atom economy of the processes is
highly undesirable.
5-Hydroxymethylfurfural (5-HMF) was included by US
Department of Energy in the previous “Top 10” list of bio-
based chemicals.1 As a result from the intense research in
this area many efficient processes for 5-HMF production
have been reported, namely from the most desirable
biorenewable feedstock, such as glucose, cellulose and
inulin. In addition, it was explored for a range of applications
by taking advantage of the rich chemistry derived by the
presence of the hydroxyl, aldehyde and furan functionalities.
However, the broad application of 5-HMF, namely for large
scale processes still suffers from several drawbacks, which
The occurrence of side reactions was observed during our
recent attempts to carry out Knoevenagel condensation of 5-
HMF with Meldrum’s acid, as recently reported for furfural.7
Under base free conditions or in presence of catalytic
amount of NaHCO3 moderate yields of 74% and 78% of 1
were achieved, respectively, accompanied by the common
dark appearance of the reaction mixtures and formation of
insoluble black tars (Table 1, entries 1 and 3). Surprisingly, in
presence of only 1% w/w of Na2S2O4 the formation of black
tars in course of the reaction was suppressed to a large
extend resulting in an outstanding yield of 96% and yellowish
appearance of the reaction mixture (Table 1, entry 2).
[a]
[b]
R. F. A. Gomes, Prof. Dr. C. A. M. Afonso
Research Institute for Medicines (iMed.ULisboa)
Faculty of Pharmacy, Universidade de Lisboa
Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
Dr. S. P. Simeonov, Dr. Y. N. Mitrev
Institute of Organic Chemistry with Centre of Phytochemistry
Bulgarian Academy of Sciences
Acad. G. Bonchev str., bl. 9, 1113, Sofia, Bulgaria
E-mail: svilen@orgchm.bas.bg
Supporting information for this article is given via a link at the
end of the document.((Please delete this text if not appropriate))
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Table 1. Knoevenagel condensation of 5-HMF with
acid and BHT catalyzes the formation of OBMF, thus leading
to significant loss of 5-HMF (Table 1, entries 3 and 4). No
dimer formation was observed in presence of urea, which is
likely to be due to the basic conditions caused by the
liberation of ammonia via formation of carbonates, as
observed by us in previous studies.11 However, significant
amount of humins was formed and only 63% 5-HMF was
preserved (Table 2, entry 6). The addition of 1% w/w ChCl
promoted considerable stabilization, effecting both the
dimerization and formation of humins, nevertheless the 5-
HMF sample significantly changed in color (Table 2, entry 7).
Both sodium metabisulfite and sodium dithionite exhibited
remarkable effect over the 5-HMF stability (Table 2, entries 8
and 9). It is worth mentioning that in both cases the visual
appearance of 5-HMF after its processing significantly
differed from all the other additives (Table 2 and see SI).
Na2S2O4 was the only additive to exhibit unprecedented
effect on the stability of 5-HMF, promoting absence of any
degradation (Table 2, entry 9). Moreover significant effect
over the long term storage was observed. After 2 months of
aging under ambient conditions crude 5-HMF sample in oil
state underwent 40% degradation in absence of stabilizer,
whereas only 18% degradation was detected in presence of
1% w/w Na2S2O4. In addition, in both cases no possible
reduction of the aldehyde function of 5-HMF was observed.12
Meldrum’s acid[a]
Reaction
mixture
5-HMF
[%][b]
Humins
[%][c]
Entry
Additive 1 [%][b]
1
None
74
10
16
2
3
Na2S2O4
NaHCO3
96
78
traces
13
traces
9
[a] Reaction conditions: 5-HMF (100 mg, 0.79 mmol), Meldrum’s
acid (110 mg, 0.79 mmol, 1 equiv.), H2O (8 mL), additive (0.01
1
equiv.), 75°C, 0.5 h. [b] Yields determined by H-NMR using 1,3,5-
trimethoxybenzene as internal standard. [c] Yield calculated from the
mass balance between 5-HMF and 1.
The lack of significant improvement of the reaction outcome
in presence of NaHCO3 led to the idea that Na2S2O4
promotes unprecedented inhibition of the side reactions
rather than efficient basic catalysis. We foresaw this property
as an unexplored strategy that may contribute in overcoming
some of the present limitations of the 5-HMF platform.
Accordingly, herein stabilization of 5-HMF in course of its
synthesis, purification, shelf life and further synthetic
transformations is described.
As reported by Galkin et al.,8 during aging in oil state, 5-HMF
tend to undergo two general degradation pathways, namely
dimerization to OBMF and not clearly understood
oligomerization to form insoluble tarry carbonaceous
materials, known as humins. Encouraged by our results we
attempted to overcome this issue by exploring several
additives for their property to preserve 5-HMF upon heating
(120°C, 4 h, neat). Given the reducing properties of Na2S2O4
we elected several commonly used antioxidants together
with choline chloride (ChCl)9 and DMSO,10 which were
reported to stabilize 5-HMF when used as solvents (Table 2).
In the absence of any additive only 37% of 5-HMF was
preserved at the end of the experiment and formation of 33%
OBMF together with 30% of humins was observed (Table 2,
entry 1). The addition of DMSO did not led to any
pronounced advantage (Table 2, entry 2). The presence of
antioxidants led to significant suppression of the formation of
humins (Table 2, entries 3, 4 and 5), which indicates that
oxidative pathways are likely to be involved in the
oligomerization of 5-HMF. However, the acidity of ascorbic
Table 2. Stability effect promoted by the addition of
additives[a]
Dimer
[%][c]
Humins
[%][d]
Entry
Additive[b]
5-HMF [%][c]
1
2
-
37
46
33
33
30
21
DMSO
Ascorbic
acid
3
42
49
8
4
5
6
7
8
9
BHT
48
71
63
86
85
43
10
0
14
6
9
19
47
Traces
9
Zn0
Urea
ChCl
Na2S2O5
Na2S2O4
100
0
0
[a] Reaction conditions: 5-HMF (100 mg, 0.79 mmol), 120°C, 4 h. [b]
1% w/w [c] Yields determined by 1H-NMR using 1,3,5-
trimethoxybenzene as internal standard. [d] Yield calculated from the
mass balance between 5-HMF and dimer.
NMR tube (Entry 1)
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and their effect over the 5-HMF stability, we believe that the
ability of Na2S2O4 to suppress possible oxidative pathways
towards humins formation combined with its mild basicity to
prevent 5-HMF dimerization is the most plausible
explanation.
NMR tube (Entry 7)
NMR tube (Entry 8)
NMR tube (Entry 9)
Table 3. Self-diffusion coefficient (*10-10, m2/s) of 1M 5-HMF
Entry
1[b]
Additive[a]
5-HMF[b]
Additive
ChCl
8.81 (9.1)
4.55
2[b]
3c]
BHT
9.41 (9.1)
8.90
-
Na2S2O4
3.67 (3.68)
[a] 1 % w/w additive. [b] Data for pure HMF is given in parenthesis.
[b] Spectra in CDCl3, 303 K. [c] Spectra in DMSO-d6, 303 K.
Further, self-diffusion NMR measurements were conducted
in order to give some insight into the observed stabilization
properties. The observed diffusion coefficient for 5-HMF was
in accord with the proposed by Galkin et al.8 self-organized
networks, whose diffusion properties show little change upon
the addition of 1% ChCl (Table 3, entry 1). However, the
significantly lower diffusion coefficient of ChCl in the
presence of 5-HMF, regardless of the similar molecular
weights of the two compounds, indicates extensive
aggregation of ChCl, presumably with the formation of high
As the stabilization effect of Na2S2O4 is not limited to the
simple disturbance of the neat 5-HMF self-arrangement in
the network one may expect that its effect will be of a much
wider scope compared to ChCl. Hence, driven by these
considerations we further explored the utility of Na2S2O4 as
stabilizer for 5-HMF synthesis, purification and various
synthetic transformations.
A long lasting challenge in the preparation of 5-HMF from
carbohydrates are the low yields sometimes observed
simultaneously with high yields of humins. A number of
research groups have reported different approaches to
overcome this problem. Sugar dehydration under aqueous
conditions with an in situ extraction of the 5-HMF in an
organic phase was intensively studied.4,13 However, although
in some examples the undesired side reactions were
suppressed to a large extent many limitations are still to
overcome. To this end, we explored the stabilization effect of
Na2S2O4 for the synthesis of 5-HMF from fructose using
simple biphasic system aq. NaCl/THF and HCl as catalyst.
The so prepared biphasic system was heated for 2h at
170°C in a sealed reaction tube. Under these conditions, the
presence of only 1% Na2S2O4 led to significant improvement
of the yield and purity (Table 4, entry 1 vs 2). The visual
inspection of the reaction`s courses revealed that in
presence of Na2S2O4 the organic phase was slightly yellow,
whereas in its absence dark brown color caused by the
formation of side products was observed. Moreover, the
appearance of the isolated crude product was an orange oil
when the reaction was carried out in presence of Na2S2O4,
while darker color and significant amount of solid black by-
products were observed in its absence.
stoichiometry
hetero-associates
with
5-HMF.
The
reorganization of the 5-HMF network is also supported by the
chemical shift changes in the presence of different amounts
of ChCl (See SI), with the most pronounced differences near
aldehyde and alcohol functions. Hence, the most plausible
explanation of the stabilization properties of ChCl is the
disturbance of the non-covalent network of the 5-HMF
molecules, as the close self-arrangement in the network is
considered favorable for the oligomerization.8 Driven by this
considerations, we anticipated that the effect of ChCl may be
limited only to the aging and thermal stability of neat 5-HMF,
as in this case the self-arrangement in the network will have
the predominant effect over the decomposition. This was
experimentally confirmed in one instance, where ChCl was
used as additive in the Knoevenagel condensation, as
expected no positive effect was observed and only 49% yield
of 1 was achieved. On the contrary, although the nature of
the Na2S2O4 hampers its direct observation in 1H
experiments, thus requiring more sophisticated approaches
(e.g. 23Na DOSY experiments), the addition of either BHT or
Na2S2O4 did not change significantly the NMR behavior of 5-
HMF (Table 3, entries 2 and 3), suggesting that indeed
different stabilization mechanism is at play. Hence, given the
similar antioxidant properties of BHT, Na2S2O5 and Na2S2O4
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Table 4. Biphasic preparation of 5-HMF from fructose[a]
Table 5. Stability effect on 5-HMF distillation[a]
Crude
5-HMF
Crude 5-HMF
5-HMF purity
Entry
Na2S2O4
Entry
5-HMF vapor
Distilled 5-HMF Na2S2O4 5-HMF [%]
yield [%][b]
[%][c]
1
1%
98
67
92
83
1
52
-
2
-
[a] Reaction conditions: Fructose (106 mg, 0.59 mmol), NaCl
aqueous solution (pH 2) (1mL), THF (2 mL), 170°C, 2 h. [b] Isolated
yield. [c] Purity determined by 1H-NMR.
2
85
2% w/w
[a] The distillations were performed at 120ºC and 5x10-4 bar using
diffusion pump.
Vacuum distillation is typically used to obtain pure 5-HMF.
However, the distillation of crude HMF was recognized to be
troublesome due to its thermal decomposition leading to the
formation of tarry carbonaceous materials. Under classical
vacuum distillation the isolated yield of pure 5-HMF from the
crude typically lies in the region of 45-60%.14 Therefore, we
further explored the effect of Na2S2O4 in solving this issue.
Two batches of 6.0 g crude 5-HMF obtained via previously
described by us protocol5b were distilled under reduced
pressure. We were pleased to observe that the presence of
only 2% w/w of Na2S2O4 promoted largely positive effect on
the outcome of the distillation leading to 85% recovery of
highly pure 5-HMF, whereas only 52% of impure 5-HMF
were recovered in its absence (Table 5, Figure 1). It is worth
mentioning that in the absence of stabilizer the NMR analysis
of the remaining residues showed mainly degradation
products, whereas in presence of Na2S2O4 the residues
contained predominantly 5-HMF (Figure 1), which was not
possible to distil due to the limitations of our distillation set
up. Hence, we anticipate that better yield may be achieved if
the distillation is carried out on a larger scale. In addition, as
described by Galkin et al.,8 the crystalline 5-HMF with purity
greater than 99.9% is a stable product, while rapid aging of
the oil form is observed even in 97-99% purity. The 5-HMF
sample obtained from the distillation in presence of Na2S2O4
met the purity requirements and smoothly solidified to form
crystalline 5-HMF, which without any further treatment was
stable under prolonged storage.
[A]
(1)
(1)
(1)
(1)
(1)
(1)
[B]
(2)
(2)
[C]
(1)
(1)
(1)
(2)
(2)
[D]
(2) + (1)
(2) + (1)
Figure 1. 1H NMR (CDCl3) of the distilled 5-HMF in presence of
stabilizer (A) and in the absence of stabilizer (B) and of the
remaining residues in presence of stabilizer (C) and in the absence
of stabilizer (D).
Encouraged by these very promising results we further
focused our attention on the effect of Na2S2O4 on the
synthetic transformations of 5-HMF, by exploring two
examples, namely Cannizzaro reaction and synthesis of
pyridinium salts.
As previously reported by us,6d 5-HMF readily undergoes
Cannizzaro reaction in presence of strong bases to yield
simultaneously the important 2,5-dihydroxymethylfurfural
(DHMF) and 5-hydroxymethyl-2-carboxylic acid (HMCA) in
up to 82% and 81% yield, respectively. However, the
formation of black side products was always observed, which
was a reason for troublesome purification of the reaction
mixtures. Under our previous conditions in presence of 1%
Na2S2O4 the formation of tars was fully omitted resulting in
quantitative yields of DHMF and HMCA (Table 6). Moreover,
we observed unexpected improvement of the reaction rate,
which allowed full conversion of 5-HMF in only 1 h compared
to 36 h in our previous studies. The isolation of both DHMF
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10.1002/cssc.201800297
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and HMFCA underwent smoothly under the previously
reported by us conditions6d to give 96% and 94% yield,
respectively.
Table 7. Stability effect on acid catalysed pyridinium salt
formation[a]
Table 6. Stability effect on Cannizzaro reaction of 5-HMF[a]
Entry
Pyridinium salt 6
Na2S2O4
6 [%][b]
Isolated
HMFCA
DHMF
[%][b]
HMCA [%][b]
1
-
60
Entry
Na2S2O4
1
-
81 (82)[c]
84 (85)[c]
2
1% w/w
88
[a] Reaction conditions: 5-HMF (100 mg, 0.79 mmol), ethanol (5
mL), 1,8-diaminooctane (171 mg, 1.19 mmol). After stirring for 30
min, formic acid aq solution (9 µL formic acid in 5mL water). [b]
Isolated Yield.
2
1% w/w
100 (96)[c]
100 (94)[c]
Albeit the use of 1%-2% w/w of Na2S2O4 could be
considered insignificant for proof-of-concept and laboratory
scale processing of 5-HMF, when considering the integration
of 5-HMF into commercial operations it is of pivotal
importance to address the production cost issues by limiting
the amount of the downstream chemicals. To this end, we
explored the minimum amount of Na2S2O4 that significantly
affects the Knoevenagel condensation (Table 8). We were
pleased to observe that even after 100-fold decrease, from
1% (Table 1, entry 2) to 0.01% w/w (Table 8, entry 3),
significant stabilization effect was still in play. As one may
expect, the effective amount of Na2S2O4 will vary according
to the different type of processes, however this result
indicates that upon optimization very low doses of Na2S2O4 are
viable. In addition, Na2S2O4 is readily available, non-toxic salt
of an industrial importance, used for instance as bleaching
agent in textile, wood pulp and paper industries. Besides
being low toxic itself, it dissociates under aerobic conditions
into non-toxic products such as sulfite, thiosulfate, and
sulfate salts.15 Hence, it may be considered as promising
stabilizer in the large scale 5-HMF processing, as the
development of recycling procedures driven by cost or
environmental issues are not of a pivotal importance.
[a] Reaction conditions: 5-HMF (100 mg, 0.79 mmol), water (0.5
mL), NaOH aq. solution (30 mg in 0.5 mL). [b] Yields determined by
1H-NMR using 1,3,5-trimethoxybenzene as internal standard. [c]
Isolated yield.
Recently, we described 6a the formation of various pyridinium
salts from the acid catalyzed condensation of 5-HMF with
primary amines. However, the final products were isolated as
black solids and in some examples only moderate yields
were achieved. Treatment with charcoal allowed to remove
the black color to a large extend. However, when stored,
even at -12°C, the so prepared pyridinium salts tend to
become black again. Therefore, the observed stabilization
effect of Na2S2O4 was foreseen by us as a promising
approach to overcome these drawbacks. To this end, as a
proof-of-concept example we elected the reaction of 1,8-
diaminooctane and 5-HMF, which was known to be
troublesome. Under the previously reported conditions, 6
was obtained as black oil in 60% yield. A simple addition of
1% w/w Na2S2O4 led to significant improvement allowing the
isolation of 6 as white solid in 88% yield (Table 7), which
maintained its color under long storage, up to 2 months.
Table 8. Dosage effect over Knoevenagel condensation[a]
Entry
Na2S2O4
0.1% w/w
0.05% w/w
0.01% w/w
1 [%][b]
5-HMF [%][c]
1
2
3
95
Traces
94
3
3
89
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Acknowledgements
The authors acknowledge Fundação para a Ciência e a
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Keywords: 5-hydroxymethylfurfural • stabilization • sodium
dithionite • biorefinery • biorenewable
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10.1002/cssc.201800297
ChemSusChem
COMMUNICATION
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Rafael F. A. Gomes, Yavor N. Mitrev,
Svilen P. Simeonov,* Carlos A. M.
Afonso*
Page No. – Page No.
Going Beyond the Limits of the
Biorenewable Platform:
Unprecedented Sodium Dithionite
Promoted Stabilization of 5-
Hydroxymethylfurfural
Text for Table of Contents
A new strategy seeking improved stability of 5-hydroxymethylfurfural during its processing was explored. Low dosages (0.01% w/w) of the readily available
sodium dithionite were observed to promote unprecedented inhibition of the common 5-hydroxymethylfurfural decomposition pathways. Our studies reviled that
the stabilization effect is highly versatile affecting 5-HMF thermal and storage stability, synthesis, distillation and synthetic transformations.
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