Self-assembled hybrid nanofibers confer a magnetorheological supramolecular hydrogel

Article abstract of DOI:10.1016/j.tet.2007.02.009

Most magnetorheological materials, composed of magnetic microparticles in a liquid, require significant amounts of magnetic particles and a large magnetic field to achieve the desired effects. Here, we report on a new type of magnetorheological materials

Full text of DOI:10.1016/j.tet.2007.02.009

Tetrahedron 63 (2007) 7349–7357
Self-assembled hybrid nanofibers confer a magnetorheological
supramolecular hydrogel*
Zhimou Yang,a Hongwei Gu,a Jun Du,b Jinhao Gao,a Bei Zhang,b Xixiang Zhangb and Bing Xua,
*
aDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
bDepartment of Physics, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
Received 2 November 2006; revised 23 January 2007; accepted 1 February 2007
Available online 7 February 2007
Abstract—Most magnetorheological materials, composed of magnetic microparticles in a liquid, require significant amounts of magnetic
particles and a large magnetic field to achieve the desired effects. Here, we report on a new type of magnetorheological materials consisting
of small amounts of magnetic nanoparticles (0.8 wt %) but exhibiting large rheological change (i.e., a gel–sol transition) upon the application of
a small magnetic field. We use self-assembly to create hybrid nanofibers, which consist of supramolecular hydrogelators and magnetic nano-
particles, as the matrices of the hydrogel. Localized in the nanofibers at a distance of 1–2 nm, the magnetic nanoparticles occupy a small volume
fraction of the hydrogel, significantly enhancing the magnetic dipole interactions between them, which results in the large magnetoresponse.
This strategy generates a hierarchical nanostructure and eliminates several drawbacks of the simple mixture of polymers with nanoparticles,
and thus provides a new methodology that uses magnetic force to control the nanostructures and properties of soft materials.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
a large rheological change should take place and result in an
MR material. Although no report has described such an MR
supramolecular hydrogel, several reports demonstrated mag-
netoresponses in polymeric gels that contain magnetic nano-
particles (e.g., ferrogels13). Although the responses are
relatively weak (i.e., the gel only changes its shape) in those
systems, these works,13–17 nevertheless, confirm that it is
possible to magnetically influence the rheological properties
of molecular aggregates in a gel by introducing magnetic
nanoparticles into the gel.
Conventionally, magnetorheological (MR) materials are MR
fluids and ferrofluids that exhibit responses to a magnetic
field but are distinct from each other.1,2 In an MR fluid,
magnetic microparticles (typical diameters in the order of
1–10 mm) are suspended in a liquid (e.g., silicon oil) under
zero field; the microparticles form fibrous aggregates aligned
with an applied magnetic field to display a dramatic change in
rheological properties. In a ferrofluid, magnetic nanopar-
ticles (with diameters in the order of 1–10 nm) are dispersed
in a liquid; the ferrofluid shows a relatively small change in
viscosity upon the application of a magnetic field because
the Brownian motion of the nanoparticles disfavors the
formation of stable fibrous aggregates. Though they seem un-
related, supramolecular hydrogels share some common fea-
tures with the MR fluids. In a supramolecular hydrogel,3–8
the self-assembly of small molecules (i.e., the hydrogelators)
forms nanofibers with an external stimulus, temperature, pH,
ionic strength, or mechanical agitation3,4 to dramatically
change the viscoelastic behavior of the materials (e.g., sol–
gel or gel–sol phase transitions). Comparable in size to hy-
drogelators, magnetic nanoparticles9–12 may cooperatively
interact with the nanofibers formed by the hydrogelators. If
a magnetic field causes formation or dissociation of the hy-
brid nanofibers of magnetic nanoparticles and hydrogelators,
In a polymeric gel mixed with magnetic nanoparticles, the
magnetic nanoparticles upon the application of a magnetic
field are unable to break up the polymer network (even
when the nanoparticles are covalently attached to the poly-
mer chains as pendants). Therefore, an insufficient interac-
tion between the magnetic nanoparticles and the polymeric
matrices of the gels limits the magnetic response and fails
to cause a large rheological change. On the other hand, ratio-
nal design of an amphiphilic molecule allows the control of
hydrogen bonding and hydrophobic interactions among the
molecules themselves and between the molecules and a sol-
vent, thus leading to self-assembled nanofibers (i.e., a type of
supramolecular architecture) of the amphiphilic molecules
in the solvent, which yield an organogel3 or a hydrogel.4 Un-
like conventional polymer networks, such nanofibers form
reversibly, providing an opportunity to incorporate magnetic
nanoparticles into them. Following this notion, we created a
new type of supramolecular hydrogel, in which the matrices
are made of self-assembled nanofibers of small molecules
*
This work was partially supported by RGC (Hong Kong), EHIA
(HKUST).
* Corresponding author. E-mail: chbingxu@ust.hk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.009

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Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
and surface-modified magnetic nanoparticles to induce
phase transitions of the hydrogel by a magnetic force. As
shown in Scheme 1, this new architecture relies on the
molecular interactions between the hydrogelators and the
magnetic nanoparticles to form hybrid nanofibers for
hydrogelation. Subjected to a non-uniform magnetic field,
the well-distributed magnetic nanoparticles in the nanofibers
respond to the magnetic field to disrupt the hybrid supra-
molecular network to lead to a gel–sol transition.
2. Results and discussions
To create the system depicted in Scheme 1, we synthesized
a small molecule hydrogelator (1) and examined its ability
to form a hydrogel. Compound 1 is a dipeptide derivative,
made by conjugating 2-(naphthalen-2-yl) acetic acid with
Phe–Phe, a diamino acid residue that has been shown to
self-assemble.18 In the molecule of 1, the napthanyl group
(C10H7CH2–) provides the hydrophobic force to enhance
self-assembly in the aqueous environment; the amide groups
on the dipeptide segment (Phe–Phe) act as both the acceptors
and the donor of hydrogen bonds. We find that 1 is an effec-
tive hydrogelator that forms a hydrogel at a concentration of
0.8 wt %, with the gel–sol transition temperature at about
323 K. A transmission electron micrograph (TEM) reveals
that 1 self-assembles to create nanofibers with widths of
18–45 nm and lengths longer than microns (Fig. 1a). These
Scheme 1. An illustration of a magnetorheological supramolecular hydrogel
based on hybrid nanofibers consisting of hydrogelators and magnetic nano-
particles.
Figure 1. Cryo-TEM images of (a) the hydrogel of 1; (b) the hydrogel formed by adding magnetite nanoparticles (0.8 wt %) into the solution of 1 (0.35 wt %);
(c, d) higher magnification of (b).

Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
7351
fibers constitute the matrices (in the form of bundles or net-
works) of the hydrogel.
hydrogel was observed over 24 h with the application of
a small magnetic force to the mixture. TEM analysis of the
mixture reveals that the nanofibers of 1 are unable to incorpo-
rate the DA–Fe3O4 nanoparticles (Fig. 2). To ensure an
adequate interaction between the nanoparticles and the
nanofibers of 1, we synthesized 2 (using dopamine as the an-
chor) to modify the surface of Fe3O4 (Schemes 2 and 3).19
The addition of the 2–Fe3O4 conjugate (0.8 wt %) into the so-
lution of 1 (0.35 wt %) converts the solution (Fig. 3a) into
a transparent hydrogel (Tgel–sol is about 325 K, Fig. 3b).
Upon the application of a small bar magnet (0.33–0.11 T,
the field is 0.33 T near the surface of the magnet), the hydro-
gel responds to the magnetic force and turns into a solution
with the nanoparticle precipitate attracted by the magnet
(Fig. 3c,d). A simple heating/cooling procedure regenerates
the hydrogel. This cycle can be repeated many times.
After proving the effectiveness of 1 in forming a hydrogel, we
added dopamine–modified Fe3O4 nanoparticles (DA–Fe3O4)
into the hydrogel (1.0 wt % of the hydrogelator). Neither
a phase transition nor a significant shape change of the
TEM analysis of the hydrogel in Figure 3b shows that the
nanofibers are from 20 to 30 nm in size (Fig. 1b) and the
nanoparticles of 2–Fe3O4, one of the structural components,
are distributed rather evenly in the nanofibers (Fig. 1c,d),
which fits the model depicted in Scheme 1. This morphology
also explains the gel–sol transition upon the application of
a small magnet. When a non-uniform magnetic field (e.g.,
as from a small bar magnet) is applied to the hydrogel, the
movement of the magnetic nanoparticles toward the magnet
causes the hybrid nanofibers to collapse. Because the remain-
ing molecules of 1 fail to reach a high enough density to form
the nanofiber matrices for gelation, the hydrogel becomes
a solution, as shown in Figure 3d and illustrated in Scheme 1.
To help elucidate the molecular details in this system, we
obtained the crystal structure of 1 (CCDC 632302: www.
ccdc.cam.ac.uk/data_request/cif) from ethanol because the
arrangement of the molecules in the nanofibers may adopt
similar molecular packing in its solid state. As shown in
Figure 4a, one molecule of 1 forms six hydrogen bonds
with four other surrounding molecules of 1, two from above
and two from below. This supramolecular arrangement not
Figure 2. TEM image of the hydrogels formed by 1.0 wt % of Nap–FF and
0.8 wt % of DA–Fe3O4 (the aggregation of the nanoparticles is caused by
cryo-drying).
O
O
O
O
H
N
O
COOH
N
H
COOH
N
H
N
N
H
O
O
O
i
ii
O
O
O
O
O
O
O
O
H
N
O
H
N
N
H
N
H
COOH
O
N
COOH
iii
H
O
i, ii
O
O
OH
OH
2
Scheme 2. Chemical structure and synthetic scheme of compound 2. (i) DCC, NHS, dimethoxy ethane; (ii) L-phenylalanine, NaHCO3, H2O/acetone; (iii) Pd/C,
methanol.

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Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
O
O
H
N
COOH
OH
i
ii
N
O
O
O
O
O
H
N
i, ii
N
H
COOH
O
1
Scheme 3. Chemical structure and synthetic scheme of compound 1. (i) DCC, NHS, dimethoxy ethane; (ii) L-phenylalanine, NaHCO3, H2O/acetone.
Figure 3. Gelation by adding magnetite nanoparticles and a magnet-induced
gel–sol transition. (a) Solution of 1 (0.35 wt %); (b) the hydrogel contain 1
and 2–Fe3O4; (c) the shape change of the hydrogel after application of the
magnet; (d) the solution of 1 and the precipitate of 2–Fe3O4.
only permits a chain-like structure, but also allows the
surface-bounded molecule of 2 on a nanoparticle to insert
Figure 4. Molecular packing of the hydrogelator 1 (a) in the crystal phase
and (b) interacting with the surface bound molecules of 2 in a plausible
model based on (a).
into the chain of 1 (Fig. 4b). With the extension of such struc-
tures, the hybrid nanofibers containing the conjugate of
2–Fe3O4 are generated, as shown in Figure 5. These hybrid
nanofibers form a hierarchical nanostructure: the self-assem-
bly of 1 affords the primary structure—supramolecular
chains; the non-covalent interactions allow the incorporation
of 2–Fe3O4 into the chains to give the secondary structure—
hybrid nanofibers. This hierarchical arrangement localizes
the magnetic nanoparticles in a small volume fraction, which
results in the observed large magnetoresponse (vide infra).
w54 K in the ZFC curve, corresponding to the unblocking
of the magnetic moment of the DA–Fe3O4 nanoparticles.20
Since magnetic nanoparticles generally exhibit uniaxial an-
isotropy, by using TBw54 K and the magnetic anisotropy
constant, K¼1.1ꢀ104 J/m3 for Fe3O4,21 we can estimate
the diameters of the nanoparticles to be 7.3 nm (based on
the relation of KV¼25KBTB20). This value matches with
the average diameter obtained from the TEM image
(7.5 nm from Fig. 1d). Above the TB, the magnetization
data follow the Curie law, Mw1/T, as seen in Figure 6b, indi-
cating very weak magnetic dipole–dipole interactions be-
tween the nanoparticles. The peak at around 287 K in the
ZFC curve is due to the transition from the solid to the hydro-
gel, at which point the particles rotate physically (in addition
to the rotation of the magnetic moments of the nanoparticles)
due to the elasticity of the hydrogel. After the onset of the
To understand the interactions between the magnetite nano-
particles within the hybrid nanofibers, we characterized the
magnetic properties of the supramolecular hydrogels con-
taining hybrid nanofibers (the ‘sample’) and its correspond-
ing control (i.e., DA–Fe3O4 mixed in the hydrogel of 1, the
‘control’). The zero-field-cooling and field-cooling (ZFC–
FC) magnetization curves (with a field of 50 Oe and from
5 to 360 K, Fig. 6a) of the control display a broad peak at

Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
7353
Figure 5. Plausible supramolecular interactions in the hybrid nanofibers.
physical rotation of the particles, the easy axes of the parti-
cles further align with the field direction, which explains the
sharp, up-displacement of the curves above the solid-to-gel
transition. The dip at 320 K originates from the gel–sol
phase transition. Near this transition, the system might un-
dergo a drastic change due to the release of stress caused
by the magnetic torque (although the elastic constant of
the gel is not large). In this process, the misaligned easy
axes of the nanoparticles cause a drop in the magnetic mo-
ment. Once the gel–sol transition is complete, the magnetic
field realigns the easy axes. Because the nanoparticles are
more physically free in the liquid phase than in the gel phase,
the magnetic moment of the sample not only recovers its
value, but also shows a small up-displacement. The overall
FC curve is typical for a non-interacting nanoparticle sys-
tem. The small, sharp dip at around 250 K is due to the freez-
ing of the liquid when the sample is cooled. At this point, the
sample undergoes a dramatic phase transition, and the phys-
ical motion of the particles is suddenly ruled out. During this
transition, the alignment of easy axes becomes frustrated,
which cause a sharp dip in the magnetization. Another
reason might be that the latent heat of the first-order phase
transition is absorbed by the magnetic nanoparticles, which
leads to a rise in the actual temperature of the nanoparticles.
This increase in the temperature of the nanoparticles would
cause a decrease in the magnetization because the magneti-
zation follows the Curie law. The alternating current (ac)
susceptibility data obtained from the control are shown in
Figure 6c. Analysis of the susceptibility data reveals that
the nanoparticles do not interact. The high temperature
data (measured from 290 to 350 K) show the superparamag-
netic behavior of the nanoparticles and the completion of the
gel–sol phase transition at 327 K.
as 1–2 nm. In this case, the magnetic dipole–dipole interac-
tion between the nanoparticles should be significant. There-
fore, one expects very different behavior from the 2–Fe3O4
nanoparticles in the sample.
As shown in Figure 6d, the ZFC–FC curves of the sample are
indeed distinct from those of the control, showing a peak at
about 16 K and an additional broad peak at about 245 K. It
is well known that a peak in a ZFC curve of a magnetic nano-
particle system is due to unblocking of the magnetic moment
(moment flipping by overcoming the anisotropy energy due
to the thermal agitation). The position and the broadness of
the peak should be determined by the size distribution of
nanoparticles and the direction of the easy axes.22 Therefore,
the peak at 16 K is due to the unblocking of the isolated (or
non-coupled) magnetic nanoparticles. From the peak temper-
ature (TB¼16 K), we can estimate that the average diameter
of these particles is about 5 nm, coinciding with the sizes of
2–Fe3O4 nanoparticles observed by TEM (Fig. 1). The broad
peak at around 245 K should be due to the unblocking of the
clusters of the magnetically coupled 2–Fe3O4 nanoparticles.
The magnetic dipole interaction between these coupled
nanoparticles is indicated in the plot of 1/M as a function of
temperature for the FC curve (Fig. 6e). Clearly, the data
follow the Curie–Weiss law, Mw1/(Tꢁq). The sign and value
of q reflect the type and strength of the interaction. Here q at
approximately ꢁ300 K indicates a strong antiferromagnetic
interaction. The broadness of the peak at 245 K should be due
to the much broader size distribution of the clusters of the
coupled nanoparticles.
The sharp increase in the magnetic moment at about 287 K
again is due to the solid-to-hydrogel transition, at which
the easy axes of the particles are aligned further by the mag-
netic field through physical rotation (which increases the
magnetization) of the nanoparticles because the hydrogel is
much softer and more elastic than the solid. Since the
clusters (or the nanoparticles) not only interact with the
As indicated by TEM (Fig. 1), the 2–Fe3O4 nanoparticles are
incorporated in the hybrid nanofibers by supramolecular in-
teractions (i.e., p–p interactions and hydrogen bondings),
which bring the nanoparticles together at a distance as small

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Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
Figure 6. The magnetic characterization of the control (a, b, c) and the sample (d, e, f). (a, d) The ZFC–FC curves measured at 50 Oe; (b, e) the 1/M vesus T
curves; (c, f) the magnetic susceptibility measured under an ac field with a field amplitude of 3 Oe.
hydrogelators in the nanofibers but also couple with each
other magnetically due to the magnetic dipole interaction,
the behavior of the nanoparticles above the blocking at
245 K does not follow the Curie law (Fig. 6e). The sharp
drop in the magnetic moment at 337 K must be due to the
gel–sol transition, which causes a dramatic frustration in
the easy axes by releasing the magnetic torque or the Brow-
nian motion of the nanofibers.
The ac susceptibility measurement also confirms the gel–sol
transition. The mechanism of the susceptibility in the dc field
and the ac field is quite different. In the dc field, the applied
field attempts to align the magnetic moment of the particles
in the field against thermal agitation and magnetic aniso-
tropy, whereas when an ac field is applied, the magnetic
moment follows the ac field and flip–flops. Therefore, a
flip–flop of the moment can be achieved via the magnetic

Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
7355
moment flipping over the anisotropy barrier and/or via phys-
ical rotation. The ac susceptibility as a function of tempera-
ture measured with different frequencies is shown in
Figure 6f. Peaks in the susceptibility curves appear at dif-
ferent temperatures for the different frequencies, which
correspond to the unblocking of the clusters of the coupled
particles as seen in the ZFC curve.22 Above the peaks, the
susceptibility decreases with increasing temperature and fol-
lows the Curie–Weiss law. The behavior of the susceptibility
is clearly distinct from that of the control in the same temper-
ature range (Fig. 6c). The sudden drop in susceptibility
appears at 337 K, where the gel–sol transition occurs. The
susceptibility indicates that the nanoparticles are restrained
in the nanofibers, and their moments follow the change in
the magnetic field only through over-barrier processes.
The nanoparticles, however, move freely when the gel
changes to a liquid (i.e., the Brownian motion can easily
destroy the response of the moment to the ac field) and con-
sequently the susceptibility drops dramatically.
hydrogelators and cause a gel–sol transition. The above
results indicate that the arrangement/localization plays
a more important role than the amount of the magnetic nano-
particles for generating magnetorheological hydrogels.
3. Conclusions
In conclusion, we have demonstrated a new type of magneto-
rheological material based on supramolecular interactions
between low-molecular-weight hydrogelators and surface-
modified magnetic nanoparticles. Compared to physically
mixing nanoparticles into covalently cross-linked polymer
hydrogels, our design has several distinct advantages: (i)
the thermodynamically favored self-assembly process23–29
permits the surface-modified magnetic nanoparticles to be
integrated into the nanofibers; (ii) the supramolecular hydro-
gel requires only a small amount of the magnetic nano-
particles to exhibit a magnetoresponse; and (iii) a small
magnetic force can modulate the self-assembled hybrid
nanofibers and induce a phase transition. The mechanism re-
vealed by the magnetic study in this work may also help in
the design of other nanoparticle-based soft materials by
using supramolecular interactions and self-assembly to gen-
erate localized/ordered domains/clusters of nanoparticles.
Since hydrogels formed by molecular self-assembly are
emerging as a new kind of biomaterial for drug deliv-
ery,30–33 tissue engineering,34–37 and biomineralization,38,39
this magnetorheological supramolecular hydrogel, which
consists of biocompatible magnetic nanoparticles, also sig-
nals the possibility of a new type of magnetoresponsive bio-
material.
Based on the magnetic characterization, we can infer the ar-
rangement of the nanoparticles in the gel phase in the control
and the sample. As illustrated in Scheme 4, the nanoparticles
homogenously distribute outside the nanofibers of the
hydrogelators in the control because of the lack of adequate
supramolecular interactions between the DA–Fe3O4 nano-
particles and the nanofibers. On the contrary, the nanopar-
ticles exclusively localize inside the hybrid nanofibers in
the sample because of the sufficient supramolecular interac-
tions between 2–Fe3O4 nanoparticles and the hydrogelators.
In other words, if we assume that the density of the hydroge-
lator is around 1 g/ml, the 0.8 wt % DA–Fe3O4 nanoparticles
disperse in a greater than 98% volume fraction of the hydro-
gel in the control, but the 0.8 wt % 2–Fe3O4 nanoparticles
aggregate in a less than 2% volume fraction of the hydrogel
in the sample. When the magnetic particles are coupled
within the nanofibers, the magnetic interaction between
the nanoparticles may serve as an extra stabilization force
to maintain the hybrid nanofibers against Brownian motion.
More importantly, upon the application of a small magnet,
these coupled magnetic nanoparticles in the sample cooper-
atively move toward the magnet and break the hybrid nano-
fibers to exhibit the gel–sol transition. In the control, under
a relatively small non-uniform magnetic field, the well-
dispersed individual magnetic nanoparticles are unable to
amass sufficient force to break the nanofibers of the
4. Experimental
4.1. General
2-(Naphthalen-6-yl)acetic acid, DCC, DMAP, N-hydroxy-
succinimide (NHS), L-phenylalanine, dopamine hydrochlo-
ride, benzyl bromine, Boc-anhydride, succinic anhydride,
and trifluoro acetic acid (TFA) were purchased from Aldrich
Co., and used without further purification. The TEM sam-
ples were prepared via cryo-drying for TEM on Philips
CM20 and JEOL 2010. (The cryo-dried samples were pre-
pared as follows: a copper grid coated with carbon was dip-
ped into the hydrogel and placed into a vial, which was
plunged into liquid nitrogen. Then, water was removed
from the frozen specimen by a freeze-drier.) 1H NMR spec-
tra were obtained on 300 MHz Bruker. All the magnetic
measurements were carried out on a Quantum Design
SQUID magnetometer (MPMP-5s) equipped with a suscep-
tometer and a 5 T magnet.
4.2. Synthesis
4.2.1. (S)-2-(2-(Naphthalen-6-yl)acetamido)-3-phenyl-
propanoic acid (1a). 2-(Naphthalen-6-yl)acetic acid
(372 mg, 2 mmol) and NHS (230 mg, 2 mmol) were dis-
solved in 40 ml of chloroform, and DCC (453 mg,
2.2 mmol) and DMAP (13 mg, 0.1 mmol) were added to
the above solution with stirring. After the reaction mixture
was stirred at room temperature for 0.5 h, the resulting solid
Scheme 4. The distribution and the localization of the magnetite nanopar-
ticles in (a) the control and (b) the sample, respectively.

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Z. Yang et al. / Tetrahedron 63 (2007) 7349–7357
was filtered off and the filtrate was evaporated in an open
dish to dryness and the crude product was used in the next
reaction without purification.
room temperature for 24 h, the resulting solid was filtered off
and the filtrate was evaporated in an open disk to dryness.
The crude product was used for the next reaction without
purification.
L-Phenylalanine (332 mg, 2 mmol) and NaHCO3 (336 mg,
4 mmol) were dissolved in 20 ml of water with stirring,
the solution of crude product (dissolved in 40 ml acetone/
ethanol¼1:1) was added, and the resulting reaction mixture
was stirred at room temperature for 24 h. The reaction mix-
ture was air-dried, then 30 ml of water was added and the
precipitate was removed by filtration. The filtrate was acid-
ified to pHw3 and the resulting product was obtained by fil-
tration, washing with water, and then dried in vacuum.
Compound 1a (white powder) was collected with 84.2%
L-Phenylalanine (166 mg, 1 mmol) and NaHCO3 (168 mg,
2 mmol) were dissolved in water (15 ml) with stirring, the
solution of crude product (dissolved in 30 ml of ethanol)
was added, and the resulting reaction mixture was stirred
at room temperature for 24 h. The reaction mixture was
air-dried, then 30 ml of water was added, and the precipitate
was removed by filtration. The filtrate was acidified to
pHw3.0, and the resulting product was isolated by filtration,
washing with water, and then dried in vacuum. Product of
392 mg (white powder) was obtained with the yield of
1
yield (561 mg). H NMR (300 MHz, DMSO-d6): d 7.84–
1
8.01 (m, 3H), 7.75 (s, 1H), 7.60–7.67 (m, 2H), 7.22–7.36
(m, 6H), 4.87–4.91 (t, 1H), 3.64–3.72 (q, 2H), 2.76–3.02
(m, 2H). 13C NMR (300 MHz, DMSO-d6): d 37.3, 42.7,
54.2, 126.0, 126.5, 126.9, 127.8, 127.9, 128.0, 128.1,
128.6, 129.7, 133.5, 134.5, 138.2, 170.4, 173.6. MS: calcd
M+¼333.14, obsd (M+1)+¼334.21.
67.5%. H NMR (300 MHz, DMSO-d6): d 8.32 (d, 1H),
8.01 (t, 1H), 7.37–7.63 (m, 15H), 7.09–7.13 (t, 2H), 6.84–
6.86 (d, 1H), 5.24–5.27 (d, 4H), 4.58 (q, 1H), 3.33–3.37 (t,
2H), 3.14–3.22 (dd, 1H), 2.96–3.04 (dd, 1H), 2.72–2.77 (t,
2H), 2.43–2.48 (t, 2H), 2.35–2.39 (t, 2H). MS: calcd
M+¼580.26, obsd (M+Na)+¼603.26.
4.2.2. (S)-2-((S)-2-(2-(Naphthalen-6-yl)acetamido)-3-
phenylpropanamido)-3-phenylpropanoic acid (1). Com-
pound 1a (333 mg, 1 mmol) and NHS (115 mg, 1 mmol)
were dissolved in dimethoxy ethane (20 ml). After the solu-
tion was cooled to 0 ꢂC in an ice-water bath, DCC (227 mg,
1.1 mmol) and DMAP (13 mg, 0.1 mmol) were added, and
the reaction mixture was stirred for 4 h at 0 ꢂC. After the re-
sulting solid was filtered off, the filtrate was evaporated in an
open dish to dryness and the crude product was used for the
next reaction without purification.
4.2.5. N-[2-(3,4-Bis-benzyloxy-phenyl)-ethyl]-succin-
amic-L-phenylalanyl-L-phenylalanine (2c). Compound
2b (290 mg, 0.5 mmol) and NHS (58 mg, 0.5 mmol) were
dissolved in dimethoxy ethane (15 ml). After the solution
was cooled to 0 ꢂC in an ice-water bath, DCC (115 mg,
0.55 mmol) and DMAP (7 mg, 0.05 mmol) were added,
and the reaction mixture was stirred for 4 h at 0 ꢂC. The re-
sulting solid was removed by filtration, and the filtrate was
evaporated in an open dish to dryness. The crude product
was used for the next reaction without purification.
L-Phenylalanine (166 mg, 1 mmol) and NaHCO3 (168 mg,
2 mmol) were dissolved in water (10 ml) with stirring, the
solution of crude product (dissolved in 20 ml of ethanol)
was added, and the resulting reaction mixture was stirred
at room temperature for 24 h. The reaction mixture was
air-dried, then 20 ml of water was added and the precipitate
was removed by filtration. The filtrate was acidified to
pHw3.0, and the resulting solid product was isolated by
filtration, washing by water, and then dried in vacuum.
The product (white powder) was purified by flash chromato-
graphy (eluant: MeOH/CHCl3¼95:5), and 360 mg of prod-
uct was obtained with the yield of 75%. 1H NMR
(300 MHz, DMSO-d6): d 7.89–8.05 (m, 3H), 7.79 (s, 1H),
7.62–7.68 (m, 2H), 7.18–7.40 (m, 11H), 4.91–4.95 (t, 1H),
4.64–4.67 (t, 1H), 3.66–3.74 (q, 2H), 2.74–3.07 (m, 4H).
13C NMR (300 MHz, DMSO-d6): d 36.9, 38.1, 41.2, 53.6,
54.6, 125.7, 126.0, 126.8, 126.9, 127.3, 127.5, 127.9, 128.1,
128.3, 128.7, 129.0, 131.2, 133.7, 138.0, 171.6, 172.4, 173.6.
MS: calcd M+¼480.20, obsd (M+1)+¼481.22.
L-Phenylalanine (83 mg, 0.5 mmol) and NaHCO3 (84 mg,
1 mmol) were dissolved in water (10 ml) with stirring, the
solution of crude product (dissolved in 20 ml of ethanol)
was added, and the resulting reaction mixture was stirred
at room temperature for 24 h. The reaction mixture was
air-dried and then water (20 ml) was added. After the precip-
itate was removed by filtration, the filtrate was acidified to
pHw3.0 and the resulting product was isolated by filtration,
washing with water, and then dried in vacuum. The product
(white powder) was purified by flash chromatography (elu-
ant: MeOH/CHCl3¼95:5), and 210 mg of product (white
powder) was obtained with a yield of 58%. 1H NMR
(300 MHz, DMSO-d6): d 7.46–7.60 (m, 10H), 7.24–7.40
(m, 10H), 7.07–7.12 (t, 2H), 6.83–6.86 (d, 1H), 5.25 (d, 4H),
4.59–4.65 (m, 2H), 3.34–3.36 (t, 2H), 2.78–3.30 (m, 4H),
2.74 (t, 2H), 2.33–2.45 (m, 4H). MS: calcd M+¼727.33,
obsd (M+Na)+¼750.32.
4.2.6. 3-[2-(3,4-Dihydroxy-phenyl)-ethylcarbamoyl]-
L-phenylalanyl-L-phenylalanine (2). Compound 2c
(145 mg, 0.2 mmol) and Pd on active carbon (29 mg,
20 wt %) were placed in a 50 ml round bottom flask. After
air was removed in vacuum, a mixture of chloroform and
methanol (10 ml, 1:1) was added through a needle and a
balloon with H2 was placed over the reaction mixture. The
reaction mixture was stirred at room temperature for 12 h.
After the catalyst was filtered off through Celite, the product
was obtained by removing the organic solvent and dried
in vacuum. Product of 109 mg (pale yellow powder) was
4.2.3. N-[2-(3,4-Bis-benzyloxy-phenyl)-ethyl]-succinamic
acid (2a). Compound 2a was synthesized by the method
described in Ref. 19.
4.2.4. N-[2-(3,4-Bis-benzyloxy-phenyl)-ethyl]-succi-
namic-L-phenylalanine (2b). Compound 2a (433 mg,
1 mmol) and NHS (115 mg, 1 mmol) were dissolved in di-
methoxy ethane (30 ml), and DCC (227 mg, 1.1 mmol)
and DMAP (13 mg, 0.1 mmol) were added to the above so-
lution with stirring. After the reaction mixture was stirred at
1
collected with a quantitative yield. H NMR (300 MHz,

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