Synthesis and Study of Molecular Assemblies Formed by 4,6-O-(2-Phenylethylidene)-Functionalized d -Glucosamine Derivatives

Article abstract of DOI:10.1021/acs.langmuir.7b01592

Low-molecular-weight gelators are interesting small molecules with potential applications as advanced materials. Carbohydrate-based small molecular gelators are especially useful because they are derived from renewable resources and are more likely to be biocompatible and biodegradable. Various 4,6-benzylidene acetal protected α-methyl 2-d-glucosamine derivatives have been found to be effective low-molecular-weight gelators. To understand the influence of the 4,6-benzylidene acetal functional group toward molecular self-assembly and to obtain effective molecular gelators, we synthesized and analyzed a new series of d-glucosamine derivatives in which the phenyl group of the acetal is replaced by a benzyl group. The homologation of the acetal protection from aromatic to aliphatic functional groups allows us to probe the effect of increasing structural flexibility on molecular self-assembly and gelation. In this study, nine representative amides and nine urea analogs were synthesized, and their gelation properties were analyzed in a series of organic solvents and aqueous solutions. The resulting amide and urea derivatives are versatile organogelators forming gels in toluene, ethanol, isopropanol, ethylene glycol, and aqueous mixtures of organic solvents. More interestingly, the amide analogs are also effective gelators for pump oil and engine oil. NMR spectroscopy at variable temperatures was used to analyze the molecular assemblies and intermolecular forces. The selected gelators with several drug and dye molecules in DMSO and water were studied for their effectiveness of encapsulation and release of these agents.

Full text of DOI:10.1021/acs.langmuir.7b01592

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Article
Synthesis and Study of Molecular Assemblies Formed by 4,6-O-
(2-Phenylethylidene) Functionalized D-Glucosamine Derivatives
Anji Chen, Surya B Adhikari, Kellie Mays, and Guijun Wang
Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b01592 • Publication Date (Web): 09 Jul 2017
Downloaded from http://pubs.acs.org on July 13, 2017
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Synthesis and Study of Molecular Assemblies Formed by 4,6-O-(2-
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Phenylethylidene) Functionalized D-Glucosamine Derivatives
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Anji Chen, Surya B. Adhikari, Kellie Mays, Guijun Wang*
Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA.
*Corresponding Author:
Guijun Wang, Ph.D., Professor
Department of Chemistry and Biochemistry
Old Dominion University
4541 Hampton Boulevard
Norfolk, VA23529-0126
Email: g1wang@odu.edu
Telephone: (757) 683-3781
Fax: (757) 683-4628
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Abstract
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Low molecular weight gelators are interesting small molecules with potential applications as
advanced materials. Carbohydrate based small molecular gelators are especially useful since they
are derived from renewable resources and are more likely to be biocompatible and biodegradable.
Various 4,6-benzylidene acetal protected -methyl 2-D-glucosamine derivatives have been found
to be effective low molecular weight gelators. In order to understand the influence of the 4,6-
benzylidene acetal functional group towards molecular self-assembly and to obtain effective
molecular gelators, we synthesized and analyzed a new series of D-glucosamine derivatives in
which the phenyl group of the acetal is replaced by a benzyl group. The homologation of the acetal
protection from aromatic to aliphatic functional groups allows us to probe the effect of increasing
structure flexibility towards the molecular self-assembling and gelation. In this study, nine
representative amides and nine urea analogs were synthesized and their gelation properties
analyzed in a series of organic solvents and aqueous solutions. The resulting amide and urea
derivatives are versatile organogelators forming gels in toluene, ethanol, isopropanol, ethylene
glycol, and aqueous mixtures of organic solvents. More interestingly, the amide analogs are also
effective gelators for pump oil and engine oil. NMR spectroscopy at variable temperatures was
used to analyze the molecular assemblies and intermolecular forces. The selected gelators with
several drug and dye molecules in DMSO and water were studied for their effectiveness of
encapsulation and release of these agents.
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Keywords:
Glucosamine, amides, ureas, self-assembly, organogelator, hydrogelator, hydrogen bonds, drug
delivery.
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Introduction
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In recent years, the preparation of soft materials using small molecule self-assembly have gained
much attention. In particular, the construction of supramolecular gels by low molecular weight
gelators (LMWGs) in organic solvents or water is an especially attractive strategy in discovering
functional new materials.1-3 The formation of supramolecular gel networks relies on noncovalent
forces such as hydrogen bonding, hydrophobic interactions, - stacking, CH- interactions, and
van der Walls forces, etc. The structures of LMWGs encompass a broad range of functionalities
and many different classes of small molecules.3-6 The molecular gels thus obtained have been
shown to have applications in biomedical research and also useful as new materials for
environmental applications and for new catalysts.7-13 Because of the broad range of applications,
many efforts have been devoted in understanding gelation mechanism and the rational design of
new functional supramolecular gelators.14-17 Among the different classes of molecular gelators,
carbohydrate based systems are especially interesting due to several factors. These include that
carbohydrate starting materials are renewable natural resources and the resulting gels are
potentially biocompatible and biodegradable. For example, N-acetyl 2-D-glucosamine can be
obtained from natural sources through degradation of chitin from shells of shrimp and other
crustaceans. The polymeric glucosamine derivatives chitin and chitosan have found many
applications as biocompatible materials.18-21 D-glucose is an abundant hexose which can be
obtained from starch and cellulose hydrolysis. D-glucose and other sugar based molecular gelators
have shown many applications for different purposes including for biomedical application and as
advanced materials for drug delivery, enzyme immobilization, and for environmental applications
and oil spill cleaning up.22-30
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Given the importance of low molecular weight organogelators and hydrogelators, we have
systematically studied the functionalization of monosaccharides especially D-glucose and D-
glucosamine to obtain effective LMWGs.31-35 As shown in Figure 1, previously we have found that
various amide and urea derivatives (1 and 2) of 4,6-O-benzylidene--D-methyl-glucopyranoside
3 are effective gelators for several organic solvents and aqueous solutions. We found that
introducing a p-methoxyl substituent to the phenyl ring also resulted in a series of effective
LMWGs.35 D-glucosamine based small molecule self-assembly will result in supramolecular
networks compounds of the aminosugar but the gel materials are reversible due to the non-covalent
nature. Due the ease of synthesis of small molecules, many pure materials can be screened and
analyzed. From the bottom up approach, we may be able to obtain novel soft materials with
desirable properties. In this study, in order to probe the structure influence towards gelation,
especially the phenyl group towards gelation and obtain effective LMWGs for potential
applications, we synthesized a new headgroup 4 which has a methylene spacer at the 4,6-protective
group. This switches aromatic aldehyde to an alkyl aldehyde which may affect the molecular self-
assembly and gelation properties. The additional methylene group increases the hydrophobicity
slightly from compound 3 (CLogP -0.56) to compound 4 (CLogP -0.18), the acylated products of
the headgroup 4 may also result in derivatives with different gelation capacity or compounds that
are more effective towards organic solvents. Through the rational design, a new series of LMWGs
could be obtained.
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Figure 1. Structures of several glucosamine derivatives.
Results and Discussions
The headgroup 4 was synthesized by a similar method as before using the N-acetyl D-glucosamine
as the starting material.34 The headgroup was then used for the synthesis of amides I and ureas II
(Scheme 1). For proof of principle studies, only a few representative functional groups were
selected for the current study and the selection of the R and R' groups was based on our previous
studies. For a comparison purpose between amides and ureas in an effort to probe the effect of
addition hydrogen bonding on gelation, the two series of compounds have similar substituents.
These include the pentyl, hexyl, heptyl, cyclohexyl, 10-undecynoyl, 6-heptynoyl, phenyl, 4-
bromomphenyl and naphthyl. Other analogs with similar structures such as terminal halides are
expected to have similar gelation properties as the alkyl analogs with comparable chain lengths.
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Scheme 1. Synthesis of amide derivatives I (8-16) and urea analogs II (17-25).
After these compounds were synthesized, their gelation properties in several solvents were tested
and the gelation results are shown in Table 1. For clarity purposes, the screening results of these
compounds in hexane, THF, and water are not listed in the table. All amides and ureas performed
similarly in these solvents, all are insoluble in hexane, water, and soluble in THF at 20 mg/mL
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concentrations. In general, the amides are more effective for aqueous mixtures and the ureas are
more effective gelators for polar organic solvents. For toluene, the amide derivatives performed
better than the urea derivatives; five amide derivatives formed gels in toluene, while only three
urea derivatives gelled toluene. For alcohols, urea derivatives are more effective gelators than the
amides. A majority of the ureas were able to form gels in ethanol, isopropanol and ethylene glycol.
And for water/DMSO mixture, water/ethanol mixtures, the amides are more efficient gelators. The
hexyl urea 18 and cyclohexyl urea 20 were also able to solidify dichloromethane (DCM) at 0 °C.
The cyclohexyl urea 20 and heptyl urea 19 were also able to form gel in THF and water mixture.
All urea analogs except the phenyl urea 23, were able to form effective gels in ethylene glycol
(EG), and six amide analogs were gelators for EG at higher concentrations than urea analogs. Low
molecular weight gelators are also being explored for their environmental applications, so we also
analyzed the gelation potentials of these compounds in pump oil and engine oil. What is interesting
is that the amides are effective gelators for these tested oils but ureas are not. The amides with
aliphatic functional groups of 6-11 carbon chains are effective gelators for both vacuum pump oil
and engine oil. It is foreseeable that linear analogs with longer alkyl chains are also likely to be
good gelators for oils. Therefore these gelators or their analog may have applications for oil spill
recovery. In contrast, none of the ureas were able to form gels in the pump oil and because of this
trend the engine oil was not tested. The change of gelation properties in oils between amides and
ureas indicated that the intermolecular interactions among urea molecules are probably too strong
and not able to form networks with oils. A majority of the gels are opaque or translucent with some
of them are transparent, a few representative photos of the gels are shown in Figure 2. Additional
images of the gels are shown in supporting information Figure S13.
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Table 1. Gelation properties of the amides (7-16) and ureas (17-25)
Engine
oil
H2O: H2O:
EtOH DMSO
THF: Pump
Tolue i-
No Structures
DCM
EtOH
EGy
H2O
(1:1)
oil
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ne
PrOH
(2:1)
(2:1)
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S
I
S
P
G20 t
I
P
S
I
I
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13 9
14
S
S
S
G20 t
P
S
P
S
P
G20 o
G10 o
G6.7 o
P
I
G10 o
I
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P
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G 6.7 o
G 20.0 o
G 6.7 o
G2.5 O
G4.0 O
G10 t G0 20 O G0 20 o
I
G10 o
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S
S
S
G10 t G10 O
S
S
S
S
G2.5 t G2.8 t
G10 o
S
S
S
G2.0 O
G6.7 O
G2.5 O
11
12
13
G 4.0 o
G 2.2 o
P
S
S
G20 t
S
I
G20 t
G10 o G4.0 o
G5.0 o G10 o
S
S
P
P
P
S
S
G5.0 t
S
S
P
I
I
S
S
14
15
Br
G20 t
I
I
S
S
S
P
G020 o
S
P
S
G3.3 o G10 t
S
P
I
I
S
16
17
G20 t
G2.2 t
I
I
N/A
G0 20 c G6.7 t G010 c G0 10 c
G2.5 t
G1.6 t
G2.2 t
G6.7 t
G3.3 c
I
I
I
I
P
I
I
I
I
I
N/A
N/A
N/A
N/A
N/A
18
19
20
21
22
P
G20 c G20 t
S
I
G15 o
G15 t
S
G0 6.7o
I
G10 t
G10 o
G3.3 t
S
S
P
G0 20 c G0 20 c
G5.0 o G5.0 t
G20 t G0 20 c G0 20 c
I
I
I
G6.7 o
P
I
I
P
P
I
P
P
P
I
I
P
P
I
I
N/A
N/A
23
24
Br
P
G5.0 t
I
I
I
I
G2.5 t
I
G3.3 t
P
I
N/A
25
All compounds were tested starting from 20 mg/mL concentration. G, stable gel at room
temperature, the numbers following G are the corresponding minimum gelation concentrations
(MGCs) in mg/mL. G0, forming a gel when the vial is cooled in an ice bath. I, insoluble. P,
precipitate. S, soluble at ∼20 mg/mL. The letter abbreviations in regular font denote the
appearance of the gel: o, opaque gel; t, translucent gel; c, transparent gel; N/A, not tested.
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Figure 2. a) A translucent gel formed by compound 11 in DMSO:H2O (v1:2) at 2.8 mg/mL; b) an
opaque gel of compound 11 in EtOH:H2O (v 1:2) at 2.5 mg/mL; c) an opaque gel of compound 21
in EtOH:H2O (v 1:2) at 5.0 mg/mL; d) a transparent gel by compound 19 in ethylene glycol at 3.3
mg/mL; e) a transparent gel formed by compound 13 in engine oil at 2.5 mg/mL.
We then analyzed the morphologies of a few representative gels using optical microscopy, these
are shown in Figure 3. The gels formed different morphology in different solvents apparently.
Compound 11 in DMSO:H2O (v 1:2) gel showed long and soft entangled fibrous network with
narrow diameters ( ~0.3 µm or less, Fig. 3a, b). The gel formed by compound 11 in isopropanol
formed more straight fibers with lengths well over 500 µm, they appear to be uniform as well with
diameters in the range of 1-1.5 µm. The gel formed by the benzamide 14 in EtOH: H2O (v 1:2) at
5.0 mg/mL (Fig. 3e, f) are somewhat shorter fibers in about 100 µm in length and formed bundles
of many fibers with similar sizes (widths ~ 0.6-1 µm). The toluene gel formed by hexyl urea
compound 18 showed long continuous and entangled fibrous network with narrow and uniform
long fibers with average 0.3 µm diameters. And the urea compound 21 in EtOH: H2O (v 1:2) also
formed fibrous type of network but with larger diameters, the fibers are also relatively shorter
(~200 µm) and wider (~1.2 µm) comparing to the others.
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Figure 3. Optical micrographs of the gels. a, b) Compound 11 in DMSO:H2O (v 1:2) at 2.8 mg/mL;
c, d) Compound 11 in isopropanol at 10 mg/mL; e, f) Compound 14 in EtOH: H2O (v 1:2) at 5.0
mg/mL; g) Compound 18 in toluene at 6.7 mg/mL; h) Compound 21 in EtOH: H2O (v 1:2) at 5.0
mg/mL.
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To analyze the gels’ stability, the gels formed by compounds 11, 12, 19 and 20 were analyzed
using a rheometer, the results are shown in Figure 4. Additional rheological experimental results
are shown in the supporting information Figures S8-S12. The Gʹ/Gʺ ratio for 11 and 20 are shown
in the supporting information Tables S1 and S2. For the oscillation frequency sweep in a range of
different frequencies, all tested gels showed that the storage modulus Gʹ is always greater than the
loss modulus Gʺ, which indicates that the gels are stable and have elastic properties.36,37 The
storage modulus Gʹ describes the elastic properties (solid-like) of the gels and the loss modulus Gʺ
describe the viscous properties (liquid-like). The rheological properties showed that the gels are
viscoelastic and remained stable when increasing the angular frequency. The DMSO/H2O gel
formed by cyclohexyl amide 11 has the largest storage modulus in this class, followed by the
cyclohexyl urea 20. At the linear viscoelastic range, the Gʹ/Gʺ ratio for 11 and 20 are similar; about
7.0 at low angular frequency and increased to 15.0 at high frequency. The large ratio indicated that
the gel has more solid like feature, when shear frequency is increased the gel become more rigid.
The urea gelator 20 has stronger intermolecular interactions and is more rigid comparing to other
systems. The EtOH/H2O gel formed by compound 12 and ethylene glycol gel formed by compound
19 are similar in their storage and loss moduli and ratio, both seem to be less rigid gels than the
DMSO/H2O gels.
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Figure 4. Rheological properties of the gels formed by compound 11 (DMSO/H2O, v1:2, 4.8
mg/mL), 12 (EtOH/H2O, v1:2, 10.0 mg/mL), 19 (ethylene glycol, 1.6 mg/mL) and 20
(DMSO/H2O, v 1:2, 5.0 mg/mL) under 1% oscillation strain.
In order to rationalize the gelation properties with the structures especially the influence of
hydrogen bonding, we studied the 1H NMR spectra at different temperatures for two representative
compounds 12 and 21 (Figures 5-7). Analysis of the 1H NMR spectra of compound 12 in CDCl3
at different temperatures can allow us to probe the hydrogen bonding effect of the gelator
molecules with themselves in organic solvents. As shown in Figure 6, the amide NH signal shifted
to lower frequencies upon increasing temperatures, with a significant amount of upfield shift from
5.85 ppm at 30 °C to 5.78 ppm at 55 °C. This indicates that intermolecular hydrogen bonding
between the gelator molecules decreased at higher temperature. No chemical shift change at the
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4,6-O- acetal signal was observed at different temperatures, while the anomeric proton has a very
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small downfield shift from 4.67 ppm to 4.68 ppm.
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Figure 5. The chemical shift assignment for the protons in the variable temperature study, the
labeled chemical shifts ( ppm) are for 30 °C.
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Figure 6. The 1H NMR spectra of compound 12 from 30-55 °C in CDCl3.
1
The effect of hydrogen bonding in ureas was analyzed using H NMR spectroscopy at different
temperatures in deuterated DMSO (Figure 7), the two urea signals shifted up field upon heating,
which reflects diminished intermolecular hydrogen bonding. The NH attached to the sugar ring
has a larger change of chemical shift of 0.07 ppm versus 0.03 ppm for the NH attached to the alkyl
chain. The largest change of chemical shift among all protons is the 3-hydroxyl proton, it shifted
from 5.09 ppm to 4.93 ppm from 30 °C to 60 °C. This agrees with what we observed before that
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3-OH group plays an important role in forming intermolecular hydrogen bonds. The 4,6 acetal
showed very little difference at different temperatures, while the anomeric hydrogen had a
downfield shift of 0.03 ppm as what was observed before.38 This reflects the strength of the
intramolecular hydrogen bonds between the 2-NH and the anomeric methoxy group, upon heating
or reducing concentrations, the intramolecular hydrogen bonding are not affected as much as the
intermolecular hydrogen bonds.
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Figure 7. The 1H NMR spectra of compound 21 in from 30-60 °C in d6-DMSO.
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As shown in Table 1, six amide derivatives and four urea derivatives formed gels in the
DMSO:H2O (v1:2) solution by the traditional heating and sonication method. For potential
biological applications, it is more desirable if the concentration of DMSO can be reduced in
aqueous solutions. We tested the gelation tendencies for amides 11, 13, 16, and ureas 20, 25 in
different combinations of DMSO with water and ethylene glycol with water. The results are shown
in Table 2. The best performing compound is the cyclohexyl amide 11, it formed gels at 1:2, 1:4
and 1:6 volume ratios of DMSO and water; the same compound worked for EG:H2O mixtures.
For application of the molecular gelators, spontaneous gelation is more desirable for many
biologically applications. Therefore we analyzed the spontaneous gelation potential for compound
11 by dissolving a small amount of gelator in DMSO at 37 °C and add water to the solution, this
compound can form stable translucent gel in 20% DMSO water mixture. The photograph of the
gels are shown in supporting information Figures S14 and S15.
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Table 2. Analysis of gelation in DMSO/water and EG/water mixtures at different ratio
DMSO:H2O
mixture
Ethylene Glycol:H2O
mixture
Compound
Structures
MGC
Ratio
MGC
G 2.9 O
PG 6.7 o
Ratio
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13
G 2.9 T
G 4.0 T
1:6
1:4
1:6
1:2
16
20
25
G 4.0 O
G 6.7 T
G 6.7 T
1:4
1:2
1:2
G 6.7 O
N/A
1:2
N/A
N/A
N/A
G: stable gel; PG: partial gel; UG: unstable gel. Gel appearance: o, opaque; c, clear or
transparent; t, translucent; N/A, not tested.
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The gel formed by compound 11 in DMSO:H2O (v1:4) was selected for testing sustained release
profile of trapped drugs from gel phase to solution phase. Naproxen and chloramphenicol (Figure
8) were selected for the study. The purpose for the characterization is to analyze the ability of the
gelator to encapsulate drug molecules in the gel matrix. The drug release was monitored by UV
absorption at certain time by transferring the supernatant with pipet to a cuvette, after each
measurement the aqueous phase was carefully transferred back to the vial. The gel photos of
naproxen release and chloramphenicol release study are shown in Figures S17-S19. The UV
spectra of naproxen release from the gel to the water phase at different time and the estimated
release% are shown in Figure 9. About 50% naproxen was released from the gel to aqueous phase
after 2 h, and after 20 h, almost all naproxen was released to the aqueous phase.
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Figure 8. Structures of the drug molecules
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Figure 9. Release of naproxen (a,b) and chloramphenicol (c,d) from gel to aqueous phase. a) UV
spectra of the naproxen, the gel is formed by 2 mg of compound 11 in 0.5 mL DMSO:H2O (v1:4)
with 0.5 mg of naproxen, naproxen control was prepared by dissolving 0.5 mg naproxen in 3 mL
of water; b) Absorbance at 330 nm at different times versus the standard was used to calculate the
% release. c) UV spectra of chloramphenicol at different times, d) % release of chloramphenicol
from gel to solution phase estimated by taking the ratio of absorbance at 278 nm with
chloramphenicol standard. The gel was formed by 2 mg of compound 11 in 0.5 mL DMSO:H2O
(v1:4) with 0.25 mg of chloramphenicol. Chloramphenicol control was prepared by dissolving
0.25 mg chloramphenicol in 3 mL of water.
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In contrast, chloramphenicol seems to be absorbed on the gel matrix more strongly (Figure 9),
about 50% drug was diffused to aqueous phase after 8 h, and in 20 h, only 60% trapped
chloramphenicol was released from the gel to solution phase. The difference of the release profile
of the two drugs could be partially due to the solubility difference in water. The gels were intact
for both samples after the 20 h period of experiment (Figure S19). The naproxen gels seem to have
lost some volume perhaps due to the better water solubility of the drug, when removing water each
time some part of the co-gel were removed. The chloramphenicol co-gel remained the same after
the 20 h of experiment. Therefore the gelator compound may be useful in encapsulation and
sustained release of chloramphenicol, it is reasonable to expect that the gelator could be used for
other neutral small molecular drugs. Also the sustained release could be controlled by changing
the gelator concentration and gel strength.
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In order to understand how the gels may interact with cationic compounds, next we analyzed the
absorption of toluidine blue dye from aqueous to gel phase through diffusion or absorption. The
gel formed by compound 16 in DMSO:H2O mixture (v1:4) at 4 mg/mL was used for the study.
Compound 16 contains a naphthyl functional group which may allow more π–π stacking
interaction with the dye’s aryl systems and allow the dye to be trapped within the gel matrix more
effectively. Toluidine blue dye has distinct UV absorptions at long wavelength region which
doesn’t interfere with the gelators and typical drugs. Adsorption of toluidine blue from aqueous
solution to the hydrogel at different time intervals was monitored by UV-Vis spectroscopy and
results are shown in Figure 10. Photographs were taken at different time course and are included
in supporting information (Figure S20). Toluidine blue is known to form dimer aggregates in
aqueous solutions, the dimer form is corresponding to the absorption max at 590 nm and the
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monomer typically has max at 626 nm.39 As shown in Figure 10, before adding to the gel matrix,
toluidine blue forms dimer predominantly which gives the absorption max at 590 nm, and a small
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amount of the dye exists in the monomer form with max at 626 nm as a shoulder peak. As the
dye starts diffusing into the gel matrix, the dimer form diminished more rapidly than the monomer
form, and after 64 h, the major absorption in the aqueous phase is the monomer form at 626 nm.
This indicates that the gel matrix is able to stabilize the monomer or breaking down the dimer
complex of toluidine blue. This implies that the gel matrix may be able to interact with the cationic
dyes by stabilizing the monomer of toluidine blue, which may have certain applications to separate
different substrates using the gels.
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3
2.5
0 h
8 h
2
16 h
24 h
1.5
32 h
48 h
64 h
1
0.5
0
400
500
600
700
800
Wavelength (nm)
Figure 10. UV-Vis spectra of toluidine blue solution above the gel of compound 16 after indicated
hours. The gel was formed by 8 mg of compound 16 in with 2 mL of DMSO:H2O mixture (v1:4),
2 mL toluidine dye solution (0.10 mM) was deposited on top of the gel.
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Conclusions
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We have rationally designed and synthesized a new series of D-glucosamine derivatives containing
4,6-O-(2-phenylethylidene) protective group as effective low molecular weight gelators. The
amide analogs are effective organogelators for toluene, isopropanol and ethylene glycol, they are
also effective for forming gels in aqueous mixtures of DMSO or ethanol. In contrast, the
corresponding urea analogs are more effective for organic solvents including dichloromethane,
toluene, ethanol, isopropanol and ethylene glycol, but not very effective in aqueous mixtures of
DMSO or ethanol. Interestingly, almost all of the synthesized amide and urea derivatives are
effective gelator for ethylene glycol. The amide analogs are also effective gelators for pump oil
and engine oils, while the urea analogs are not effective gelators for oils and they also showed
diminished gelation tendencies in aqueous solutions. The insertion of a methylene group at the
4,6-O-benzylidene acetal protective group increases the hydrophobicity of the derivatives.
Therefore, the analogs are expected to be more effective in trapping organic solvents; polar
substituents can be introduced to the molecules to obtain other molecular gelators for water or
aqueous solutions in the future. In summary, the insertion of methylene group between phenyl and
the hydroxyl groups didn’t affect the gelation properties, most analogs are able to form stable gels
in at least one tested solvents. 1H NMR spectroscopy at variable temperature shows the importance
of hydrogen bonding for both amide and urea analogs. The compounds that are effective gelators
in DMSO and water mixtures were studied for their potential in encapsulating naproxen and
chloramphenicol drug molecules. The results obtained here are expected to be useful models for
drug delivery using gel matrix formed by molecular gelators.
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Experimental section:
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General method and materials:
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Reagents and solvents were used as they were received from the suppliers. All purification was
conducted by flash chromatography using 230-400 mesh silica gel obtained from Natland
International Corporation, unless otherwise noted. The solvent systems used for chromatography
are all in volume ratio. The solvent mixtures for all gelation test are also in volume ratios. NMR
analysis was conducted using a 400 MHz Bruker NMR spectrometer. Melting point measurements
were carried out using a Stuart automatic melting point apparatus SMP40. Rheology measurement
was done using a HR-2 Discovery Hybrid Rheometer from TA instrument and a 25 mm Peltier
Plate.
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General method for characterizations of molecular assemblies
Gelation testing: About 2 mg of dried compound was placed in a 1 dram glass vial and the
corresponding solvent was added to obtain a concentration of 20 mg/mL. The mixture was then
heated until the solids were fully dissolved, sometimes sonication was needed to dissolve the
sample, then the solution was allowed to cool to room temperature and let stand for 15 minutes.
After this period, if the sample is clear, this is recorded as soluble, if solid reappeared, this is
recorded as precipitate; if the sample formed a gel, then the via is inverted and if there is no solvent
flowing this indicated that a stable gel is formed, otherwise this is recorded as unstable gel. The
stable gel was then serial diluted till the minimum gelation concentration, which is the
concentration prior to unstable gelation, is obtained. Additional gel photos are included in Figure
S13.
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For testing different aqueous solutions: 2 mg of each tested compound (11, 13, 16, 20, and 25) was
weighed and transferred to a 1 dram vial following by adding 0.1 mL of DMSO/Ethylene glycol.
The mixture was then heated until the solids were fully dissolved. To this mixture 0.2 mL of water
was added, serial dilution was then performed. The vial was inverted to prove that a stable gel was
formed. Some photos of stable gels at maximum amount of water versus organic solvents are
shown in Figure S14.
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Spontaneous gelation test: 2 mg of compound 11 was weighed and transferred to a 1 dram vial
followed by adding 0.1 mL of DMSO. Compound was gradually dissolved when the mixture was
immersed in 37 °C water bath. A 1 mL syringe containing 0.4 mL of water at pH 7 with a needle
was used to transfer water by slow injection of water through needles to the bottom of the vial
during a 2 minutes injection time. After completely adding 0.4 mL of water, the syringe was
removed gently from the mixture. The mixture was left at the 37 °C water bath for 10 minutes
before it was removed and let standing at rt for 1 hour. Then the vial was inverted and if there is
no solvent flowing this indicated that a stable spontaneous gel is formed. Some photos of stable
gels are shown in Figure S15.
Optical microscopy studies: A small amount of the gels was placed on a clean glass slide and
this was observed under an Olympus BX60M optical microscope and the Olympus DP73-1-51
high performance 17MP digital camera with pixel shifting and Peltier cooled. The imaging
software for image capturing is CellSens 1.11. For aqueous DMSO solvent, the gel was left air dry
for a day or so, for other solvents the slides were observed directly.
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Rheological analyses: Rheological behavior of gel was investigated by HR-2 Discovery Hybrid
Rheometer from TA instrument with the TRIOS software. A sample (approximately 1 mL of the
gel) was placed on the steel plate of the rheometer. The cone geometry is 25-mm peltier plate and
with a gap of 100 µm. The experimental temperature was 25 °C, the sample was subjected to
amplitude sweep for oscillation strain from 0.125% to 10%. A frequency sweep was then
performed for the sample in the range of 0.1 to 100.0 rad/s for angular frequency. The results were
expressed as the storage modules (G′) and loss modules (G″) as a function of the angular frequency.
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Naproxen trapping and release: A gel was prepared in a 1 dram via using 2 mg of compound 11
and 0.5 mg of naproxen sodium and 0.5 mL DMSO:H2O (v1:4), after a stable gel formed and the
gel was left undisturbed for 2 hours, 3 mL of water at pH 7 was added to the top of the gel carefully.
Naproxen release from the gel was monitored by UV absorption at certain time by transferring the
supernatant with pipet to a cuvette, after each measurement the aqueous phase was carefully
transferred back to the vial and placed on top of the gel again till the next measurement. The UV
spectra of the pure naproxen and pure gelator in the test solvent system were also recorded.
Chloramphenicol trapping and release: The gelator-drug co-gel was prepared by using 2 mg of
compound 11 in 0.5 mL DMSO:H2O (v1:4) with 0.25 mg of chloramphenicol. Chloramphenicol
control was prepared by dissolving 0.25 mg chloramphenicol in 3 mL of water. The experiment
was performed similarly to the naproxen release study. Additional figures are included in the
supporting information Figures S16-S19.
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Dye diffusion and absorption studies: Toluidine blue dye was selected for the diffusion study
with the gel formed by compound 16. A gel was prepared in a 1 dram vial using 8 mg of compound
16 in 2 mL of DMSO:H2O mixture (v1:4) the concentration of the gelator is 4 mg/mL. After a
stable gel was formed and the gel was left at room temperature for 2 hours, 2 mL of toluidine blue
aqueous solution (0.1 mM) was added dropwise onto the top of the gel. Adsorption of toluidine
blue from aqueous solution to the gel at different time intervals was monitored by UV-Vis
spectroscopy and results are shown in Figure 10. Photographs were taken at different time course
and are shown in Figure S20.
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Synthesis and characterization data of headgroup 4, amides 7-16, and ureas 17-25.
Synthesis of the 4,6-O-(2-phenylethylidene) protected headgroup 4
To a 50 mL round bottom flask, compound 6 (α: β = 9:1)34 (2.00 g, 8.50 mmol, 1 equiv), phenyl
acetaldehyde dimethyl acetal (1.83 mL, 11.05 mmol, 1.3 equiv), PTSA monohydrate (162 mg,
0.85 mmol, 0.1 equiv) and 10 mL anhydrous DMF were added in the given order. The resulting
mixture was stirred at 70 °C for 6 hours under N2 atmosphere. Then the reaction mixture was
neutralized by adding NaHCO3 (143 mg, 1.70 mmol, 0.2 equiv) and stirring was continued at rt
for 30 minutes. After removing DMF under reduced pressure, workup was performed using
dichloromethane (DCM, 30 mL x 3) and water (10 mL). The combined organic layer was dried
over Na2SO4 (anhydrous), filtered and concentrated to afford crude product. The crude product
was recrystallized using absolute EtOH/Hexanes mixture to afford 1.80 g (5.34 mmol, 63%) white
solid as part of the pure product. The mother liquor residue was concentrated and purified by flash
chromatography on silica gel using DCM to 5% MeOH/DCM to give 0.55 g (1.63 mmol, 19%)
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pure compound 7 (0.55 g, 1.63 mmol, 19%), Rf = 0.5 in 5% MeOH/DCM. The final yield of
compound 7 is 82% (2.35 g, 6.97 mmol), mp 245.0-247.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.31-
7.20 (m, 5H, Ar-H), 5.88 (d, J = 8.4 Hz, 1H, -NH-), 4.77 (dd, J = 6.5, 3.8 Hz, 1H, Ph-CH2-CH-),
4.67 (d, J = 3.8 Hz, 1H, H-1), 4.20-4.08 (m, 2H, H-2, H-6a), 3.84 (dd ~ t, J = 9.6 Hz, 1H, H-3),
3.69-3.60 (m, 1H. H-5), 3.48 (dd ~ t, J = 10.3 Hz, 1H, H-6b), 3.39-3.33 (m, 4H, -OCH3, H-4), 3.05
(dd, J = 14.2, 3.8 Hz, 1H, Ph-CHa-CH-), 2.93 (dd, J = 14.2, 6.5 Hz, 1H, Ph-CHb-CH-), 2.06 (s,
3H, Ac); 13C NMR (100 MHz, CDCl3) δ 171.7, 136.1, 129.7, 128.3, 126.6, 102.8 (Ph-CH2-CH-),
98.7 (C-1), 81.6 (C-4), 71.1 (C-3), 68.4 (C-6), 62.3 (C-5), 55.2 (-OCH3), 54.2 (C-2), 40.9 (Ph-
CH2-CH-), 23.3 (Ac); LC-MS m/z calcd for C17H24NO6 [M + H]+ 338.2 found 338.1.
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Deacetylation reaction was performed either in thermal or microwave condition using KOH in
ethanol under refluxing conditions similarly as previous reported to afford compound 4 from
compound 7 (500 mg, 1.48 mmol, 1 equiv) as a while solid in quantitative yield (437 mg, 1.48
mmol). mp 128.0-130.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H, Ar-H), 4.75 (dd, J
= 6.2, 4.1 Hz, 1H, Ph-CH2-CH-), 4.64 (d, J = 3.1 Hz, 1H, H-1), 4.10 (dd, J = 10.2, 4.9 Hz, 1H, H-
6a), 3.71-3.63 (m, 2H, H-5, H-3), 3.47 (dd ~ t, J = 10.4 Hz, 1H, H-6b), 3.38 (s, 3H, -OCH3), 3.26
(dd ~ t, J = 9.3 Hz, 1H, H-4), 3.03 (dd, J = 14.2, 4.1 Hz, 1H, Ph-CHa-CH-), 2.94 (dd, J = 14.2, 6.2
Hz, 1H, Ph-CHb-CH-), 2.75 (s, 1H, H-2), 2.03 (s, 3H, -OH, -NH2); 13C NMR (100 MHz, CDCl3)
δ 136.2, 129.6, 128.3, 126.6, 102.7 (Ph-CH2-CH-), 101.2 (C-1), 81.5 (C-4), 71.6 (C-3), 68.7 (C-
6), 62.6 (C-5), 56.7 (C-2), 55.4 (-OCH3), 40.9 (Ph-CH2-CH); LC-MS m/z calcd for C15H22NO5 [M
+ H]+ 296.1 found 296.1.
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General procedure for the amide derivatives 8-16
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The corresponding acyl chloride (or made from carboxylic acid reacting with oxalyl chloride) (1.2
equiv) was added dropwise to a solution composed of compound 4 (75 mg, 0.254mmol, 1.0 equiv),
DIEA (2.0 equiv) and anhydrous THF at 0 °C in an ice bath. The resulting mixture was stirred at
0 °C or brought to rt for a few hours (4 to 7 h). THF was removed using the rotavap. Workup was
done using DCM and water or 5% NaHCO3 (aq.). The combined organic layer was dried over
Na2SO4 (anhydrous), filtered and concentrated to give the crude, which was purified by column
chromatography to afford corresponding amide as the desired product. The detailed procedures for
compounds 8 and 12 are given, the others only the characterization data are included since they
were synthesized by the same procedure.
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Synthesis of pentyl amide derivative 8
To a scintillation vial, valeric acid (0.034 mL, 0.305 mmol, 1.2 equiv), 3 mL DCM (anhydrous),
1 drop DMF (anhydrous) were added in the given order. The resulting mixture was stirred at 0 °C
for 10 minutes followed by adding oxalyl chloride dropwise (0.026 mL, 0.305 mmol, 1.2 equiv)
and then was stirred at rt for 4 hours. The above prepared acyl chloride and was added at 0 °C
dropwise to another solution containing compound 4 (75 mg, 0.254 mmol, 1 equiv), DIEA (0.044
mL, 0.280 mmol, 1.1 equiv) in 3 mL THF (anhydrous). Reaction mixture was stirred at rt for 7
hours. THF was removed using the rotavap. Workup was done using DCM (10 mL x 3)/water (10
mL). The combined organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated
to give the crude, which was purified by column chromatography using eluent from pure DCM to
5% MeOH/DCM to afford off-white solid (88 mg, 85%) as the desired product (Rf = 0.5 in 5%
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Langmuir
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MeOH/DCM); mp 206.0-208.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 5.86 (d, J =
8.5 Hz, 1H, -NH-), 4.77 (dd, J = 6.4, 3.8 Hz, 1H, Ph-CH2-CH-), 4.67 (d, J = 3.9 Hz, 1H, H-1),
4.20-4.07 (m, 2H, H-2, H-6a), 3.83 (dd ~ t, J = 9.6 Hz, 1H, H-3), 3.68-3.60 (m, 1H. H-5), 3.48 (dd
~ t, J = 10.3 Hz, 1H, H-6b), 3.40-3.34 (m, 4H, -OCH3, H-4), 3.23 (s, 1H, -OH), 3.05 (dd, J = 14.2,
3.8 Hz, 1H, Ph-CHa-CH-), 2.93 (dd, J = 14.2, 6.4 Hz, 1H, Ph-CHb-CH-), 2.25 (t, J = 7.6 Hz, 2H, -
CH2-C=O), 1.70-1.58 (m, 2H), 1.43-1.31 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.9, 136.1, 129.7, 128.3, 126.6, 102.8, 98.7, 81.6, 71.2, 68.4, 62.3, 55.2, 54.1, 40.9,
36.4, 27.6, 22.3, 13.7; LC-MS m/z calcd for C20H30NO6 [M + H]+ 380.2, found 380.2.
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Synthesis of hexyl amide derivative 9
The crude product was purified by column chromatography using hexane:acetone:DCM (2:1:1) to
afford the compound 9 as a white solid (85 mg, 85%), Rf = 0.5 in hexane:acetone:DCM = 2:1:1,
mp 203.0-205.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.33-7.19 (m, 5H), 5.85 (d, J = 8.4 Hz, 1H, -
NH-), 4.77 (dd, J = 6.4, 3.7 Hz, 1H, Ph-CH2-CH-), 4.66 (d, J = 3.8 Hz, 1H, H-1), 4.20-4.07 (m,
2H, H-2, H-6a), 3.82 (dd ~ t, J = 9.6 Hz, 1H, H-3), 3.69-3.61 (m, 1H, H-5), 3.48 (dd ~ t, J = 10.3
Hz, 1H, H-6b), 3.41-3.33 (m, 4H, -OCH3, H-4), 3.05 (dd, J = 14.2, 3.7 Hz, 1H, Ph-CHa-CH-), 2.93
(dd, J = 14.2, 6.4 Hz, 1H, Ph-CHb-CH-), 2.25 (t, J = 7.6 Hz, 2H, -CH2-C=O), 1.71-1.59 (m, 2H),
1.39-1.25 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.9, 136.1, 129.7,
128.3, 126.6, 102.8, 98.7, 81.6, 71.2, 68.4, 62.3, 55.2, 54.1, 40.9, 36.6, 31.3, 25.3, 22.3, 13.9; LC-
MS m/z calcd for C21H32NO6 [M + H]+ 394.2, found 394.2.
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