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(Figure 2; the insert). The NOESY NMR spectrum of the
the contribution of the side-reactions. Under the optimized
neat 5-HMF exhibited NOE correlations between every pair
of non-equivalent protons, suggesting the existence of a more
closely packed arrangement of molecules connected by
a hydrogen-bonding network (see the Supporting Informa-
tion).
reaction conditions efficient recycling was demonstrated:
(82 Æ 10)% yield was observed in 15 cycles (see Figure S2). In
all cycles, 99% pure 5-HMF was obtained, and it formed
crystals upon cooling. Also, it could be recrystallized to obtain
the crystalline product with greater than 99.9% purity (see
the Supporting Information). The reaction was successfully
carried out with fructose and cellulose as starting materials
and led to 85 and 50% yields of 5-HMF, respectively. Storage
of crystalline 5-HMF for 1 month at room temperature did
not lead to product decomposition, and the compound
remained pure as confirmed by NMR and MS analysis.
These results are in sharp contrast to the behavior of oily 5-
HMF, in which aging and decomposition rapidly took place in
a short period of time.
The observed strong influence of water can be explained
by taking into account the molecular arrangement of 5-HMF
in solution (Figure 2) as it may facilitate the side-reactions.
Continuous removal of water during synthesis decreased the
effect of the product degradation process and increased the
yield. The studied catalytic system utilized an important
advantage of ionic liquids—low vapor pressure and high
thermal stability combined with unique molecular level
properties.[13]
1H and 13C{1H} NMR spectra of 5-HMF in the neat oil
state exhibited rather narrow lines with full width at half
maximum (FWHM) at less than 10 Hz, which corresponds to
T2* relaxation times in the range of 50–70 ms. This range is
close to the typical values for tissues and other specimens with
constrained molecular mobility.
As determined by NMR spectroscopy, aggregation of 5-
HMF in solution leads to the formation of a self-organized
network. The close arrangement of the molecules in the
network is favorable for dimerization and further oligomeri-
zation. This observation may explain unique properties of 5-
HMFand its tendency toward rapid aging and decomposition.
In fact, dimerization and oligomerization takes place in
already geometrically preorganized system, thus the oligo-
merization process can be very facile. In such a supramolec-
ular network of molecules in solution, a much stronger
influence of the acidic impurities and other reaction con-
ditions should be observed. In the crystalline form, molecules
of 5-HMF also exhibit intermolecular hydrogen bonds,[12]
however restricted molecular mobility ensures stability of
crystallized 5-HMF.
For monitoring carbohydrate conversion and 5-HMF
decomposition processes, we developed a straightforward
procedure for the analysis of 5-HMF-containing systems using
NMR spectroscopy directly in ionic liquids (see the Support-
ing Information). Spectral analysis of the reaction mixture
provided a reliable picture of catalytic performance and
eliminated the influence of product decomposition during
isolation. A number of optimizations were carried out and
revealed a strong influence of water on the reaction yield and
selectivity. To achieve selective conversion of carbohydrates
into 5-HMF, continuous removal of excess of water was
essential.[9j] Conventional stirring of the reaction mixture
using a magnetic stirrer bar or mechanical stirrer did not give
desired efficiency of the catalytic process, even under vacuum
(see Figure S4 in the Supporting Information). However,
continuous surface renewal during exposure to vacuum
substantially improved the reaction outcome. Continuous
surface renewal was efficiently achieved using a rotary
evaporator for the synthesis of 5-HMF. Carrying out the
synthetic procedure in the rotary evaporator simplified the
reaction setup and product isolation. Solvent recycling during
the extraction process was carried out using the same rotary
evaporator. This option is a convenient and affordable reactor
which allows the dehydration reaction to proceed in a vacuum
under very efficient surface-renewing mixing conditions (see
Figure S4).
The selectivity of 5-HMF formation from glucose is much
lower as compared to fructose because of harsh reaction
conditions and decomposition of 5-HMF during the synthetic
process.[8,9] As we established, the fact can be associated with
the formation of oligomeric products resulting from hydro-
gen-bonding networks involving 5-HMF. In such a case
protection of O(6)-position of the carbohydrate (which is
involved in hydrogen-bonding to the hydroxymethyl group in
5-HMF) should effect side-reactions.
Indeed, the concept is very practical since O(6)-protected
glucose is easily accessible (Scheme 3). We have found that 6-
O-TBDPS-d-glucopyranose undergoes conversion into 5-
Scheme 3. Highly selective conversion of O-protected d-glucopyranose
to O-protected 5-HMF. a) TBDPSCl, DMAP, Py, RT, 24 h;
b) CrCl3·6H2O, [BMIM][Cl], methyl isobutyl ketone, 1208C, 1 h.
BMIM=1-n-butyl-3-methylimidazolium, DMAP=4-(N,N’-dimethyl-
amino)pyridine, Py=pyridine, TBDPS=Ph2tBuSi.
(TBDPS-oxymethyl)furfural using a known CrCl3 catalyst.
The product was obtained in 81% yield upon isolation. For
comparison, conversion of unprotected glucose with the same
catalytic system results in much lower yields of 40–50%.[11a] In
some cases high yields were observed according to NMR and
HPLC analyses.[1–8] However, the yield of pure isolated 5-
HMF can be significantly lower because of degradation
during the isolation process. In such a case, handling O-
protected sugar can noticeably improve the process.
Use of a large amount of the catalyst and heating above
808C led to a decrease in the yield of 5-HMF as a result of the
formation of byproducts. Another important factor was the
ratio between the amounts of the carbohydrate substrate and
ionic liquid. The concentration of the dissolved carbohydrate
affected the viscosity of the reaction mixture and influenced
The absence of a free hydroxy group prevents formation
of a hydrogen-bonding network, thus suggesting a plausible
influence on oligomerization during the conversion process.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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