Mild One-Step Synthesis of 4,6-Benzylideneglycopyranosides from Aromatic Aldehydes and Gelation Abilities of the Glucose Derivatives

Article abstract of DOI:10.1002/ejoc.201500658

We report herein an efficient one-step synthesis of 4,6-benzylidene glycoside derivatives from aromatic aldehydes bearing electron-donating or -withdrawing groups as well as polymerisable monomer groups. Glucose, mannose and galactose derivatives could also be used successfully. Several of the glucose derivatives thus obtained acted as gelators for various solvents, including water. 4-(n-Butoxybenzylidene)glucose derivative 3a produced both a clear squalane gel and a hydrogel at 0.1 wt.-%. Furthermore, 3-(n-butoxybenzylidene)glucose derivative 3i produced a clear organogel and an opaque hydrogel. The critical gelation concentration (CGC) of 3i in squalane was determined to be 0.02 wt.-%, which is one of the lowest CGC values reported so far. The organogels, hydrogels and aqueous solution gels produced from 3a and 3d exhibited thixotropy. The strength and thixotropy of the organo- and hydrogel produced from 3a were estimated by a rheometer. The gel morphologies were observed by field-emission and wet-scanning electron microscopy, and the self-assembly modes were analysed by XRD. We have concluded that super-gelators can be created by this method. An efficient one-step synthesis of 4,6-benzylidene glycosides from aromatic aldehydes under mild conditions has been achieved. Some of the glucose derivatives synthesised by this method produced clear organo- and hydrogels with thixotropic properties. The critical gelation concentrations of the gels were below 0.1 wt.-%.

Full text of DOI:10.1002/ejoc.201500658

FULL PAPER
DOI: 10.1002/ejoc.201500658
Mild One-Step Synthesis of 4,6-Benzylideneglycopyranosides from Aromatic
Aldehydes and Gelation Abilities of the Glucose Derivatives
Fumiyasu Ono,*[a] Osamu Hirata,[b] Keiko Ichimaru,[a] Koichiro Saruhashi,[b]
Hisayuki Watanabe,[a,b] and Seiji Shinkai[c]
Keywords: Carbohydrates / Protecting groups / Self-assembly / Gels / Nanostructures
We report herein an efficient one-step synthesis of 4,6-benz-
ylidene glycoside derivatives from aromatic aldehydes bear-
ing electron-donating or -withdrawing groups as well as
polymerisable monomer groups. Glucose, mannose and ga-
lactose derivatives could also be used successfully. Several
of the glucose derivatives thus obtained acted as gelators for
various solvents, including water. 4-(n-Butoxybenzylidene)-
glucose derivative 3a produced both a clear squalane gel and
a hydrogel at 0.1 wt.-%. Furthermore, 3-(n-butoxybenzylid-
ene)glucose derivative 3i produced a clear organogel and an
opaque hydrogel. The critical gelation concentration (CGC)
of 3i in squalane was determined to be 0.02 wt.-%, which is
one of the lowest CGC values reported so far. The organo-
gels, hydrogels and aqueous solution gels produced from 3a
and 3d exhibited thixotropy. The strength and thixotropy of
the organo- and hydrogel produced from 3a were estimated
by a rheometer. The gel morphologies were observed by
field-emission and wet-scanning electron microscopy, and
the self-assembly modes were analysed by XRD. We have
concluded that super-gelators can be created by this method.
protected. First reported by Evans,[3] the reaction generally
proceeds in two steps via the dimethyl acetal of the aro-
matic aldehyde.[4–6]
Introduction
The natural abundance of sugars highlights their impor-
tance in nature. For example, d-glucose, which is one of
the major monosaccharides, provides energy to the cells. In
addition, oligo- and polysaccharides also play very impor-
tant roles in living systems. For example, sugar chains on a
cell’s surface can act as recognition sites for other cell sur-
faces, viruses and toxins.[1,2] To understand the functions of
sugars in vivo, their availability through an efficient syn-
thetic process is critical. The reaction steps should be as
short as possible in terms of time and cost. The syntheses
of oligo- and polysaccharides are typically accompanied by
the repetitive protection and deprotection of the monosac-
charide units. One of the most important protection meth-
ods for monosaccharides is the preparation of their 4,6-
benzylidene derivatives, which are useful as building blocks
in the extension of sugar chains. In these reactions, two
hydroxy groups in the monosaccharide are regioselectively
It has previously been reported that this protection reac-
tion has been achieved through one-step processes.[7–28]
However, these transformations require high temperature,[7]
extended reaction times,[8–15] metal catalysts[16–27] or stoi-
chiometric catalysis.[28] Recently, the organocatalytic syn-
thesis of 4,6-benzylidene glycosides from aromatic alde-
hydes in one step under mild conditions was reported by
Schmidt and co-workers.[29] However, unidentified peaks
1
were observed in the H NMR spectra of some of the gly-
cosides under these reaction conditions. It is unclear
whether these unidentified peaks were impurities or dia-
stereo- or regioisomers. In this paper we report the efficient
synthesis of various 4,6-benzylidene glycosides catalysed by
p-toluenesulfonic acid (pTsOH) under mild conditions. We
explored the gelation abilities of several of the glucoside
derivatives in a variety of organic and aqueous solvent sys-
tems because gelators containing naturally occurring sugars
are expected to be useful for applications that require envi-
ronmentally friendly properties and functions. The gelation
properties were thoroughly investigated by various electron
microscopic, rheometric and X-ray diffraction methods.
[a] Advanced Materials Research Laboratory, Collaborative
Research Division, Art, Science and Technology Center for
Cooperative Research, Kyushu University,
4-1 Kyudai-Shinmachi, Nishi-ku, Fukuoka-city,
Fukuoka 819-0388, Japan
E-mail: ono@astec.kyushu-u.ac.jp
http://www.astec.kyushu-u.ac.jp/e/collaborative/materials.html
[b] Nissan Chemical Industries, Ltd.,
10-1 Tsuboi-Nishi 2-chome, Funabashi-city, Chiba 274-8507,
Japan
Results and Discussion
[c] Institute of Systems, Information Technologies and
Nanotechnologies (ISIT),
Synthesis of 4,6-Benzylidene Glycosides
4-1 Kyudai-Shinmachi, Nishi-ku, Fukuoka-city,
Fukuoka 819-0388, Japan
The reaction of a monosaccharide with an aromatic alde-
hyde under Brønsted acid catalysis to yield a 4,6-benzyl-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500658.
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F. Ono et al.
FULL PAPER
idene glycoside is reversible, as shown in Scheme 1a. If the creased by the conversion of the water liberated from the
water can be removed, the reaction proceeds to generate the reaction between the aldehyde and monosaccharide into
desired product. Triethyl orthoformate, added as a water ethyl formate and ethanol in the presence of triethyl ortho-
scavenger,[30] facilitates glycoside formation with concomi- formate.
tant conversion to ethyl formate and ethanol (Scheme 1, b).
Based on the results of the addition of triethyl ortho-
Performing the reaction under reduced pressure allows the formate, we applied the pTsOH-catalysed synthesis of 4,6-
removal of these two products from the reaction medium.
benzylidene glycopyranosides to various combinations of
aromatic aldehydes and monosaccharides. The results are
summarised in Table 1 and Schemes 2–4. As noted above,
in the absence of triethyl orthoformate, only a low conver-
sion was achieved (entry 3). In contrast, in the presence of
1.2 equiv. of triethyl orthoformate, the reaction afforded
product 3a in a high yield (entry 4). An attractive feature
of this process is that it uses a simple extractive work-up.
The reactions of 2a with electron-rich aromatic aldehydes
1c and 1d proceeded efficiently to afford the corresponding
glucose-based products 3c and 3d[31] in high yields (entries 2
and 5). The reactions of aromatic aldehydes bearing heat-
sensitive acrylate and methacrylate groups (1g and 1h) also
proceeded smoothly to afford the corresponding glucopyr-
anosides 3g and 3h in moderate and high yields, respectively
(entries 7 and 8). The reactions of benzaldehyde 1b and aro-
matic aldehydes with electron-withdrawing groups 1e and
1f as well as the regioisomeric 1i proceeded at 40 °C to af-
ford the corresponding glucose-based products 3b and 3i in
Scheme 1. Reversible reaction of aromatic aldehyde 1 and methyl
α-d-glucopyranoside (2a).
We first examined the effects of the triethyl orthoformate
additive. The reaction between 4-n-butoxybenzaldehyde
(1a) and methyl α-d-glucopyranoside (2a; 1.1 equiv.) cata-
lysed by pTsOH (2.5 mol-%) in DMF at room temperature
1
under reduced pressure was monitored by H NMR spec-
troscopy, with periodic sampling to follow the conversion
of aldehyde 1a into product 3a. The reaction profiles as a
function of time for different quantities of triethyl ortho-
formate are presented in Figure 1. In the absence of triethyl
orthoformate the reaction proceeded slowly with conver-
sions of 8% at 30 min, 12% at 1 h and 15% at 2 h. Under
these conditions, the reaction achieved equilibrium at
around 2 h. However, with 0.5 equiv. of triethyl ortho-
formate, the rate of the reaction was accelerated and the
conversions were 50% at 30 min, 52% at 1 h and 55% at
2 h. Moreover, when the amount of triethyl orthoformate
was increased to 1.0 equiv., the conversions increased to
73% at 30 min, 85% at 1 h and 84% at 2 h. In excess
(1.2 equiv.), the conversion of aldehyde 1a into product 3a
was 78% at 30 min, 92% at 1 h and 95% at 2 h. These re-
sults indicate that the ratio of the reaction product is in-
Table 1. Reactions of aromatic aldehydes 1 and methyl α-d-gluco-
pyranoside (2a).
[a] Yields of isolated products 3, determined on the basis of the
amount of 1. All the reactions were carried out by using aldehyde
1 (10 mmol) and methyl α-d-glucopyranoside (2a; 11 mmol) in the
presence of pTsOH·H2O (0.25 mmol) and triethyl orthoformate
(10 mmol) in DMF (10 mL) unless otherwise noted. [b] Reaction
carried out for 2 h at 40 °C and 50 hPa (by rotary evaporator). [c]
Reaction carried out with 12 mmol triethyl orthoformate for 2 h at
room temp. and 3–5 hPa. [d] No triethyl orthoformate was used.
[e] Reaction concentration on the basis of the amount of 1d was
0.5 m (20 mL of DMF). [f] Reaction carried out for 5 h at 40 °C
and 50 hPa (by rotary evaporation).
Figure 1. Effect of triethyl orthoformate addition on the conversion
of 1a into 3a: none (blue), 0.5 equiv. (purple), 1.0 equiv. (green),
1.2 equiv. (red) and 1.5 equiv. (orange).
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Synthesis of 4,6-Benzylideneglycopyranosides
high yields and 3e and 3f in moderate yields (entries 1, 6, 7 LMWGs have been reported. For example, Sureshan et al.
and 10). To conduct this reaction under reduced pressure, prepared gels by using mannitol derivatives that could selec-
flasks containing mixtures of the aldehyde, monosacchar- tively and easily remove oil from a mixture of oil and seawa-
ide, triethyl orthoformate and pTsOH in DMF were con- ter,[44] Yamanaka and co-workers reported that
a
nected to a rotary evaporator.
hydrogel prepared from a tris-urea derivative with glucose
The reactions of other monosaccharides with electron- moieties can function as a matrix for the electrophoresis
rich aromatic aldehydes proceeded at room temperature and of acidic native proteins[45] and Maruyama and co-workers
afforded the corresponding mannose (3j and 3k)- and ga- reported that a gelator precursor, capable of forming a
lactose (3l)-based products in moderate yields (Scheme 2 hydrogel after activation by a cancer-related enzyme, in-
and Scheme 3). In addition, the reactions of glucose 2d and duced selective cytotoxicity towards cancer cells.[46]
galactose 2e containing an unprotected hydroxy group at
LMWGs of 4,6-benzylidene monosaccharides were first
the anomeric position with 4-n-butoxybenzaldehyde (1a) reported by Shinkai and co-workers in 1998,[47] and since
also proceeded at room temperature to afford the corre- then a number of 4,6-benzylidene-glycoside-type gelators
sponding products 3m and 3n (Scheme 4).
have been studied.[48–55] Recently, we reported the gelation
ability of 4,6-benzylidene mannose derivatives, which were
able to gel various organic solvents and aqueous solu-
tions.[56] It is particularly worth noting that the critical gela-
tion concentration (CGC) of the 4,6-(p-butoxybenzylidene)-
mannose derivative in squalane was 0.025 wt.-%. In this pa-
per, we describe the gelation abilities of several glucoside
derivatives in various solvents, including water.
The gelation abilities of 3a, 3d and 3i with an electron-
donating group and 3f with an electron-withdrawing group
were determined in 19 different solvents, including water
and six aqueous mixtures. In each case, 1.6–20 mg of the
glucose derivative were immersed in 1.0–8.0 mL of the de-
sired solvent in a sealed vial while being heated. The sample
Scheme 2. Reactions of alkoxy-functionalised aromatic aldehydes 1
and methyl α-d-mannopyranoside (2b).
Table 2. CGCs for transparent gels and qualitative assessment[a] if
the CGC could not be determined.
Entry Solvent
CGC [wt.-%]
3a
3d
3i
3f
1
2
3
4
octane
1.0
0.25
0.1
0.5 TL
0.25
0.25
0.25
0.5
0.1 PG
P
P
P
P
Scheme 3. Reaction of 4-n-methoxybenzaldehyde (1c) with methyl
α-d-galactopyranoside (2c).
cyclohexane
squalane
squalene
0.25
0.02[b]
0.25
5
toluene
1.0
1.0
S
2.0
6
SH245
0.25
0.5
0.05
P
7
olive oil
1.0
1.0
2.0
1.0 OG
8
9
IPM
1.0
S
S
S
S
S
S
S
1.0 TL
S
S
S
S
1.0
S
S
S
S
S
S
S
P
S
NC
S
S
NC
S
NC
chloroform
ethyl acetate
acetone
cyclohexanone
acetonitrile
DMSO
EtOH
MeOH
ethylene glycol
glycerol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Scheme 4. Reaction of 4-n-butoxybenzaldehyde (1a) with glucose
2d or galactose 2e.
2.0 TL
S
2.0 TL[c]
2.0 TL[c]
0.05
P
S
S
S
S
S
2.0 OG
P
0.1
S
Gelation Abilities of the Glucose Derivatives
1.0
0.25 OG
S
2.0 OG
P
S
water
IS
0.05
DMSO/H2O (75:25)[d]
It would be convenient if the easily and efficiently synthe-
sised molecules displayed some desirable functions suitable
for practical applications. Therefore we examined the gela-
tion abilities of the glucose derivatives synthesised by this
procedure. Low-molecular-weight gelators (LMWGs) can
gel various organic solvents and aqueous solutions.[32–43] In
a gel, LMWGs self-assemble into three-dimensional net-
work structures. Recently, as a result of their facile prepara-
DMSO/H2O (50:50)[d] 0.5
0.25 TL 2.0 OG 2 OG
DMSO/H2O (25:75)[d] 0.25
0.5 TL
1.0 TL
0.05
1.0 OG 0.5 OG
S
S
EtOH/H2O (75:25)[d]
S
S
EtOH/H2O (50:50)[d] 2.0 TL
EtOH/H2O (25:75)[d] 0.25 TL
2.0 OG
1.0 TL
0.25 OG 1.0 OG
[a] TL, translucent gel; OG, opaque gel; S, solution; IS, insoluble;
P, precipitation; PG, partial gel; NC, needle crystal. [b] After 2 h.
[c] After 24 h. [d] The numbers in parentheses indicate the ratio of
tion and diverse self-assembly morphologies, a number of the solvent mixture (v/v).
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F. Ono et al.
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vial was cooled to room temperature and then inverted after ose-derived gelators is affected by van der Waals and
1 h. We classified the obtained results as follows: trans- hydrogen-bonding interactions in both oil and water.
parent gel, translucent gel, opaque gel, precipitate, clear
solution, needle crystal or suspension. The results are sum-
marised in Table 2.
Compounds 3a and 3d successfully gelled aliphatic
hydrocarbons,
toluene,
decamethylcyclopentasiloxane
(SH245), olive oil and isopropyl myristate (IPM) with
CGCs of less than 1 wt.-%. In addition, 3a was able to gel
ethylene glycol, water and some aqueous solutions. Com-
pound 3d was able to gel acetonitrile, ethylene glycol, eth-
anol and methanol. Notably, 3a was able to produce in
squalane a transparent organogel as well as a transparent
hydrogel at 0.1 wt.-% (Figure 2, a,b). Compound 3i, a re-
gioisomer of 3a, was also able to gel aliphatic hydrocarbons,
SH245, olive oil and IPM. Surprisingly, the CGC of 3i in
squalane was 0.02 wt.-% (Figure 2, c), one of the lowest
CGCs of the LMWGs prepared from carbohydrate com-
pounds in organic solvents. In contrast, compound 3f did
not show gelation ability in as many solvents as observed
in the cases of 3a and 3d because of the high crystallinity
of 3f.
Figure 3. (a) Thixotropic behaviour of the cyclohexane gel prepared
from 3a at 0.25 wt.-%, (b) after application of shear stress and (c)
after 1 h at room temp.
Figure 4. (a) Thixotropic behaviour of the hydrogel prepared from
3a at 0.5 wt.-%, (b) after application of shear stress and (c) after
1 h at room temp.
Figure 5. (a) Thixotropic behaviour of the gel in 50% ethanol aque-
ous solution gel prepared from 3d at 0.5 wt.-%, (b) after application
of shear stress and (c) after 1 h at room temp.
Figure 2. (a) Squalane gel and (b) hydrogel prepared from 3a and
(c) squalane gel prepared from 3i.
The strength and thixotropic properties of the squalane
gel and the hydrogel prepared from 3a were estimated by
rheology.[66] The frequency sweep curves for the squalane
gel and the hydrogel are shown in Figure 6a,b. The storage
elastic moduli (GЈ) and the loss elastic moduli (GЈЈ) are in-
dependent of the angular frequency (ω), and the values of
Thixotropic Behaviour
Thixotropy is the property exhibited by certain gels on GЈ are consistently larger than the values of GЈЈ at a given
becoming liquid when stirred or shaken. This phenomenon frequency. These results indicate that both the squalane gel
is characteristically observed for LMWGs and has attracted and the hydrogel of 3a exhibit typical gel-like behav-
considerable interest from gel scientists because of its sig- iour.[14,44,67,68] Plots of GЈ and GЈЈ against the strain ampli-
nificant relationship with biological self-healing processes tude (γ) at ω = 1.0 rads–1 are shown in Figure 6 (c, d). In
such as the repair of injured muscular and neural fibres. the case of the squalane gel, the value of GЈ was about
The property is also of interest for industrial applications 4600 Pa up to γ = 1.58% (Figure 6, c), whereas in the case
in materials such as cosmetics, paints, biomaterials and of the hydrogel, the value of GЈ was about 2300 Pa up to γ
foodstuffs.[57–65] We examined this behaviour for glucose de- = 1.58% (Figure 6, d). These values of GЈ indicate a gel of
rivatives 3a and 3d. After gel formation by heating, the moderate strength.[67]
cyclohexane gel of 3a was permitted to rest for 1 h at room
Next, we measured the time dependence of the storage
temperature before a shear stress was introduced by vortex elastic modulus (GЈ) during the re-formation of the gels pre-
mixing. After allowing the vial to stand again for 1 h at pared from 3a at 0.5 wt.-% after the application of shear
room temperature, it was inverted. The regeneration of the stress. In the squalane gel, after applying a constant strain
gel indicated that the sample prepared from 3a was thixo- of 1000% for 10 s to destroy the gels, the gel re-formed
tropic (Figure 3). The hydrogel prepared with 3a also dem- within 4 h (Figure 7, a). On the other hand, in the hydrogel,
onstrated thixotropy (Figure 4). To the best of our knowl- after the application of shear stress, the hydrogel re-formed
edge, this is the first observation of thixotropic behaviour within 20 min (Figure 7, b). Additionally, the destruction
by both the organogel and the hydrogel of the same gelator. and re-formation processes of the gels could be repeated
Moreover, even the gel prepared in 50% aqueous ethanol three times. These results also clearly indicate that the
exhibited thixotropy (Figure 5). These results reveal that, in squalane gel and the hydrogel prepared from 3a exhibit
the course of gel re-formation, the self-assembly of the gluc- thixotropic properties.
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Synthesis of 4,6-Benzylideneglycopyranosides
Figure 6. Rheological studies of the squalane gel and the hydrogel prepared from 3a at 0.5 wt.-%, (a,b) Frequency sweep and (c,d) strain
sweep of the squalane gel and hydrogel, respectively. GЈ (red); GЈЈ (blue).
Figure 7. Time dependence of the storage elastic modulus during
the re-formation of the gels prepared from 3a at 0.5 wt.-% after
application of shear stress: (a) squalane gel and (b) hydrogel: before
shear stress (see arrow), first cycle (1), second cycle (2) and third
cycle (3).
Figure 8. (a) Photograph of the cyclohexane gel prepared from 3a
and (b,c) FESEM images of its xerogel.
Morphologies of the Gels
We investigated the morphologies of the cyclohexane gels
and hydrogels prepared from 3a, 3d and 3i by using field-
emission scanning electron microscopy (FESEM) and low-
vacuum SEM (wet-SEM; see Figures 8–12). For the
FESEM measurements, xerogels were obtained by freezing
and pumping the gels for 5–10 h. The xerogels were placed
on carbon tape and observed without metal deposition. For
the wet-SEM measurements, the hydrogels prepared from
3a and 3i were placed on carbon tape and observed directly
at 50 Pa. The FESEM images of the xerogels prepared from
3a and cyclohexane display three-dimensional entangled
networks of fibres with diameters of 40–70 nm (Figure 8).
Additionally, the images for 3i display a similar three-
dimensional entangled fibrous network with fibre diameters
of 30–60 nm (Figure 9). In contrast, the SEM images
for 3d reveal a sheet-like structure (Figure 10). These dif-
ferent morphologies can be explained by the stronger
Figure 9. (a) Photograph of the cyclohexane gel prepared from 3i
and (b,c) FESEM images of its xerogel.
Figure 10. (a) Photograph of the cyclohexane gel prepared from 3d
and (b,c) FESEM images of its xerogel.
Next, the wet-SEM images of the hydrogels prepared
van der Waals interactions between the longer alkyl chains from 3a and 3i were obtained (Figures 11 and 12). For the
in 3d compared with in 3a and 3i.
transparent hydrogel formed from 3a, we observe a cloudy
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F. Ono et al.
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image derived from a very thin fibrous network, whereas for than the length of one molecule. Therefore 3a in the cyclo-
the opaque hydrogel formed from 3i, a three-dimensional hexane gel adopts a one-dimensional arrangement by the
entangled fibrous network can be clearly observed. The interdigitation of the gelator with a slight overlap of the
FESEM image of the xerogel prepared from the hydrogel glucose moieties as a result of hydrogen-bonding interac-
of 3a displays a three-dimensional entangled fibrous net- tions (Figure 14). The weak peak at 1.59 nm has been at-
work with fibre diameters of 35–60 nm, whereas the net- tributed to the aliphatic unit. This analysis is also supported
work of the xerogel formed from 3i was comprised of fibres by the crystal structure of methyl 4,6-O-benzylidene-α-d-
with a width of 60–200 nm.
glucopyranoside.[53]
Figure 11. (a) Photograph of the hydrogel prepared from 3a,
(b) wet-SEM image of the hydrogel and (c) FESEM image of its
xerogel.
Figure 14. Molecular length of 3a by CPK molecular modelling
based on PM3 calculations and the proposed molecular packing of
3a in the cyclohexane gel and the hydrogel.
The PXRD pattern of the hydrogel-based xerogel of 3a
reveals broad peaks at d = 3.32 and 1.79 nm. Similarly to
the cyclohexane-based gel, the length of the peak at 3.32 nm
lies between one and two lengths of the gelator molecule 3a;
the peak at 1.79 nm has been attributed to the approximate
length of one molecule. Gelator 3a in the hydrogel therefore
adopts a one-dimensional arrangement with interdigitation
of the gelator molecules with the overlap of their alkoxy
chains driven by van der Waals interactions. We previously
reported that the self-assembly modes of the 4,6-benzyl-
idene mannose derivative were different in the organogel
and the hydrogel with the major driving forces being
hydrogen-bonding interactions in the organogel and
van der Waals interactions in the hydrogel.[56] Interestingly,
the PXRD pattern of the hydrogel of the mannose deriva-
tive reveals periodic diffraction peaks corresponding to hex-
agonal packing, whereas that of the hydrogel of the glucose
derivative 3a reveals simple peaks, as in the case of the or-
ganogel. As a result, the hydrogel and organogel prepared
from 3a consist of very thin supple fibrous networks. This
is the reason why the hydrogel formed from 3a is clear.
Figure 12. (a) Photograph of the hydrogel prepared from 3i,
(b) wet-SEM image of the hydrogel and (c) FESEM image of its
xerogel.
Powder X-ray Diffraction Measurements
The powder X-ray diffraction (PXRD) patterns of the
xerogels prepared from the cyclohexane gel and the hydro-
gel of 3a show periodic reflection peaks (Figure 13). The
differences in the peak patterns reflect the different self-as-
sembly modes of 3a in the cyclohexane gel and hydrogel.
The PXRD pattern of the cyclohexane-based xerogel exhib-
its broad peaks at d = 3.45 and 1.59 nm. The main peak at
3.45 nm is less than twice the length of the molecular length
of 3a (1.78 nm by CPK molecular modelling), but longer
Figure 13. PXRD patterns of the xerogels of the cyclohexane gel
(red) and hydrogel (blue) prepared from 3a.
Figure 15. PXRD patterns of the xerogels of the cyclohexane gels
prepared from 3a (red) and 3d (blue).
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Synthesis of 4,6-Benzylideneglycopyranosides
formed with a Yanaco MT-5 or MT-6 CHN-CORDE instrument
at the Center of Elementary Analysis, Kyushu University.
1H-NMR Monitoring of the Conversion to Methyl 4,6-O-(4-n-But-
Next, we used PXRD to compare the long spacing dis-
tances of 3a and 3d in the xerogels prepared from cyclohex-
ane gels (Figure 15). The peaks of 3a and 3d at 3.45 and
5.20 nm, respectively, indicate that the radius of the fibre
grows with an increase in the length of the alkoxy chain
attached to the aromatic ring.
oxybenzylidene)-α-D-glucopyranoside (3a): 4-n-Butoxybenzaldehyde
(1a; 10 mmol) was added to a suspension of methyl α-d-gluco-
pyranoside (2a; 11 mmol) and p-toluenesulfonic acid monohydrate
(0.25 mmol) in anhydrous DMF (10 mL) and the mixture was
stirred for 5 min at room temp. Then, if necessary, triethyl ortho-
formate was added dropwise to the suspension at room temp., and
the reaction mixture was stirred under reduced pressure. Aliquots
were removed after 0.25, 0.5, 1, 2, 3 and 4 h. The samples were
quenched with saturated NaHCO3 and extracted with ethyl acetate.
The extracts were concentrated and redissolved in CDCl3. The con-
Conclusions
We have demonstrated an efficient one-step synthesis of
4,6-benzylidene glycosides from aromatic aldehydes under
mild conditions that requires only a simple extractive treat-
ment after the reaction. The key factors for the success of
this reaction are the addition of triethyl orthoformate to
scavenge the liberated water and mild vacuum conditions
to remove the resulting ethanol and ethyl formate. The reac-
tion tolerates aldehydes bearing electron-donating and
-withdrawing groups as well as polymerisable monomer
groups; glucose, mannose and galactose derivatives are suit-
able reaction partners.
Several glucose derivatives synthesised by this procedure
were found to act as gelators in various solvents, including
water. In particular, 4-n-butoxybenzylidene glucose deriva-
tive 3a produced a clear squalane gel as well as a hydrogel
at 0.1 wt.-%. Furthermore, 3-n-butoxybenzylidene glucose
derivative 3i also produced a clear organogel and an opaque
hydrogel. The CGC of 3i in squalane was 0.02 wt.-%, which
is one of the lowest values reported for an oil gelator. The
FESEM images of the xerogels of cyclohexane gels pre-
pared from 3a and 3d display a three-dimensional entangled
fibrous network and a sheet-like structure, respectively. This
difference in morphology is caused by the strength of the
van der Waals interactions between the gelator molecules,
which depend on the length of the alkoxy chains. The self-
assembly of gelator 3a in the organogel and hydrogel occurs
by different modes, as revealed by PXRD. Additionally, the
organogels and hydrogels produced from 3a and 3d exhibit
thixotropy. The rheological behaviours of the organogel and
hydrogel produced from 3a also clearly indicate that these
gels have thixotropic properties. To the best of our knowl-
edge, this is the first observation of thixotropic behaviour
by both the organogel and the hydrogel of the same gelator.
These studies have demonstrated the potential utility of
these easily accessible materials and we are now investiga-
ting the unique physical properties of the various glycoside
derivatives synthesised by this procedure.
1
versions from aldehyde 1a to products 3a were determined by H
NMR spectroscopy.
Synthesis of Methyl 4,6-O-(4-n-Butoxybenzylidene)-α-D-glucopyr-
anoside (3a): 4-n-Butoxybenzaldehyde (1a; 10 mmol) was added to
a suspension of methyl α-d-glucopyranoside (2a; 11 mmol) and p-
toluenesulfonic acid monohydrate (0.25 mmol) in anhydrous DMF
(10 mL) and the mixture was stirred for 5 min at room temp. Then
triethyl orthoformate (12 mmol) was added dropwise to the suspen-
sion at room temp. The reaction mixture was stirred for 15 min at
room temp. and then for 2 h under reduced pressure (3–5 hPa) at
room temp. Thereafter, the reaction was quenched with saturated
NaHCO3 and extracted with ethyl acetate. The extracts were
washed with brine, dried with Na2SO4, filtered and concentrated
under reduced pressure. Hexane was added to the resulting crude
product and the mixture was stirred overnight at room temp. The
suspension was filtered and the solids were dried in vacuo. The
desired product 3a was obtained as a white powder (3.2 g, 89%).
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.7 Hz, 2 H), 6.88
(d, J = 8.7 Hz, 2 H), 5.47 (s, 1 H), 4.78 (d, J = 4.1 Hz, 1 H), 4.27
(dd, J = 4.1, 9.6 Hz, 1 H), 3.99–3.86 (m, 3 H), 3.83–3.67 (m, 2 H),
3.61 (dt, J = 3.7, 9.2 Hz, 1 H), 3.51–3.40 (m, 4 H), 2.84 (br. s, 1
H), 2.36 (br. d, J = 9.2 Hz, 1 H), 1.81–1.70 (m, 2 H), 1.48 (sext, J
= 7.3 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.8, 129.3, 127.5, 114.3, 101.9, 99.7, 80.9, 72.8, 71.8,
68.9, 67.7, 62.4, 55.5, 31.2, 19.2, 13.8 ppm. HRMS (EI+): calcd.
for C18H26O7 [M]+ 354.1679; found: 354.1681. C18H26O7 (354.40):
calcd. C 61.00, H 7.40; found C 61.03, H 7.38.
The synthesis procedures and characterisation data for the other
carbohydrate derivatives are described in the Supporting Infor-
mation.
Gelation Tests with Organic Solvents, Mixed Solvents, and Water:
The gelator and solvent were mixed in a vial sealed with a cap and
heated in a dry bath until the solid dissolved. The solution was
then cooled to room temp. If a stable gel was observed at this stage,
the CGC value was noted and listed in Table 1.
Rheological Measurements: Rheological measurements were con-
ducted with an Anton Parr MCR 301 rheometer (Anton Paar Ja-
pan K.K). The gelator and solvent were mixed in a vial sealed with
a cap and heated in a dry bath until the solid dissolved. The solu-
tion was poured onto the sample stage and kept for 15 min at
25 °C. A cone-type plate with a diameter of 50 mm and a tilt angle
of 1.0° was used for all the measurements. The measurements were
Experimental Section
Instrumentation: 1H and 13C NMR spectra were acquired with a
Bruker AVANCE 500 or JEOL JNM-ECS 400 spectrometer at the
Analytical Centre in the Fukuoka Industry-Academia Symphon- performed at 25 °C in strain sweep modes (0.01–100%) at a con-
icity facility. Chemical shifts are reported in ppm relative to an
internal standard: tetramethylsilane or [D7]DMF for 1H NMR and
CDCl3 or [D7]DMF for 13C NMR. EI and FAB mass spectra were
recorded with a JEOL JMS-700 at the Evaluation Center of Mate-
rials Properties and Function, Institute for Materials Chemistry
and Engineering, Kyushu University. Elemental analyses were per-
stant angular frequency of 6.28 rads–1 and in frequency sweep
modes (0.0628–628.0 rads–1) at a constant strain of 0.1%. The
thixotropic properties of the gels were examined as described below.
A constant strain of 1000% was applied to the fresh gel for 10 s to
destroy the gels by shear stress. The recovery of the storage modu-
lus was monitored at 6.28 rads–1 under a low shear force of 0.1%
Eur. J. Org. Chem. 2015, 6439–6447
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6445

F. Ono et al.
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SEM: FESEM imaging was performed with a Hitachi SU-8000
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Acknowledgments
The authors thank Ms. Makiko Fukuda for support with the rheo-
logical measurements. The authors thank Dr. Midori Watanabe,
Center of Advanced Instrumental Analysis, Kyushu University, for
support with the wet-SEM observations. The authors thank Mr.
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Received: May 21, 2015
Published Online: August 6, 2015
Eur. J. Org. Chem. 2015, 6439–6447
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6447