Self-assembly of thermotropic liquid-crystalline folic acid derivatives: Hydrogen-bonded complexes forming layers and columns

Article abstract of DOI:10.1039/b103168f

Folic acid derivatives having 2-(3,4-dialkoxyphenyl)ethyl moieties have been found to exhibit thermotropic liquid-crystalline behavior. Smectic and discotic phases are observed for these compounds over wide temperature ranges. X-Ray diffraction and infrar

Full text of DOI:10.1039/b103168f

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Self-assembly of thermotropic liquid-crystalline folic acid
derivatives: hydrogen-bonded complexes forming layers and
columns{
Kiyoshi Kanie,a Masayuki Nishii,a Takayasu Yasuda,a Takashi Taki,a Seiji Ujiieb and
Takashi Kato*a
aDepartment of Chemistry and Biotechnology, Graduate School of Engineering, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
E-mail: kato@chiral.t.u-tokyo.ac.jp
bDepartment of Material Science, Shimane University, Matsue, Shimane 690-8504, Japan
Received 10th April 2001, Accepted 23rd May 2001
First published as an Advance Article on the web 2nd October 2001
Folic acid derivatives having 2-(3,4-dialkoxyphenyl)ethyl moieties have been found to exhibit thermotropic
liquid-crystalline behavior. Smectic and discotic phases are observed for these compounds over wide
temperature ranges. X-Ray diffraction and infrared measurements show that the formation of the smectic and
discotic phases is due to the ribbon- and disk-like structures of the pterin rings of folic acid, respectively. The
smectic phase is changed to a hexagonal columnar phase by the addition of alkali metal salts. This behavior is
attributed to the change of the hydrogen-bonded structures from ribbon to disk induced by the ion–dipolar
interactions.
external stimuli or to the atmosphere by dynamic change of
their self-assembled structures.
Introduction
The use of molecular self-organization processes is a useful
strategy for the development of novel functional materials
having nanometre or micrometre scale order.1 Therefore,
molecules capable of forming self-assembled and self-organized
structures have attracted a great deal of attention in materials
chemistry.1 Biomolecules are a treasury of hydrogen-bonded
molecules.2,3 The wide diversity, high selectivity, and dynamic
properties of the hydrogen bonding play a crucial role in
providing self-assembling, self-replicating, and reproducing
abilities to organisms. To obtain functional materials such as
liquid crystals,4 the formation of hydrogen-bonded assemblies
is one of the most important approaches.5,6 For example, the
hydrogen bonding between pyridines and carboxylic acids has
been shown to be advantageous for spontaneous formation of
supramolecular calamitic liquid crystals.5 Dynamic structures
exhibiting association and dissociation of the hydrogen
bonding can be achieved for these liquid crystals.5a–e Hydrogen
bonding has also been applied to form discotic liquid-
crystalline assemblies.7
In the present study, we use the self-assembling abilities of
folic acid for the development of novel thermotropic liquid
crystals. To induce thermotropic liquid crystallinity, we have
introduced 2-(3,4-dialkoxyphenyl)ethyl groups into the
L-glutamic acid moiety of folic acid.12 We describe the
Here, we intend to introduce calamitic and/or discotic
anisotropy into biomolecules. We focused on folic acid as a
building block for new thermotropic hydrogen-bonded liquid
crystals. Folic acid is an important biologically active
molecule.8 Its alkali metal salts are known to show lyotropic
liquid-crystalline phases in water.9 The generation of a
lyotropic hexagonal columnar phase is attributed to the
hydrogen-bonded discotic tetramer formation of the pterin
(2-aminopteridin-4-ol) moieties.9 The pterin ring of folic acid
also has the potential to show two hydrogen-bonded self-
assembling patterns as shown in Fig. 1.10,11 If we can control
the nature of the spontaneous formation of the two hydrogen-
bonded patterns, novel materials with dynamic functions will
be obtained. These materials are expected to respond to
{Basis of a presentation given at Materials Discussion No. 4, 11–14
September 2001, Grasmere, UK.
Fig. 1 Hydrogen-bonded ribbon-like (A) and disk-like (B) aggrega-
tions of the pterin ring of folic acid.
DOI: 10.1039/b103168f
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This journal is # The Royal Society of Chemistry 2001
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Table 1 Isolated yields of compounds 1, 5, and 6
Isolated yields(%)
n
5
6
1
6
11
70 (5a)
80 (5b)
66 (6a)
56 (6b)
65 (1a)
40 (1b)
74 (DL-5b)
80 (5c)
86 (5d)
80 (DL-6b)
16a (6c)
61b (6d)
54 (DL-6d)
24 (DL-1b)
42 (1c)
29 (1d)
14
18
85 (DL-5d)
49 (DL-1d)
aThe reaction was carried out in benzene in lieu of EtOAc–EtOH.
Chart 1
bReaction conditions: CH2Cl2–EtOH–HCO2H~25 : 5 : 1 (wt/wt/wt).
carbodiimide hydrochloride (EDC) in the presence of 4-(N,N-
dimethylamino)pyridine (DMAP). To obtain 6, the benzyloxy-
carbonyl group of 5 was successively hydrogenated with 10%
palladium activated on carbon (Pd/C) under a hydrogen
atmosphere. In this step, to suppress side reactions such as
intramolecular amidation and/or ester-exchange, the reaction
was carried out at 50uC within 3 h. In some cases, especially for
5d, the hydrogenation did not proceed effectively. The addition
of formic acid into the reaction mixture solved the problem.17
The details for the hydrogenation are summarized in the
Experimental section. An N,N-dimethylformamide (DMF)
solution of 7 was treated with isobutyl chloroformate in the
presence of triethylamine to prepare mixed anhydride 8. The
mixture was added to a THF solution of 6 and reacted in
the dark under an argon atmosphere for 4 days. Purification of
the crude mixture by flash column chromatography on silica gel
followed by recycling preparative gel permeation chromato-
graphy (GPC) afforded the desired compounds 1a–d as
analytically pure forms. The introduction of the trifluoroacetyl
group on the N10 atom of the pteroic acid improved the solu-
bility in organic solvents and accelerated nucleophilic sub-
stitution of the nitrogen atom of the glutamate at the carboxy
carbon.
Scheme 1 Reagents and conditions: i) CnH2nz1Br (2.2 mol), K2CO3
(4.0 mol), DMF, 80 uC, 1 d, 75–91%; ii) LiAlH4 (1.1 mol), THF, 0 uC,
3 h, 92–100%.
synthesis, thermotropic liquid-crystalline behavior, and struc-
tural change of folic acid derivatives.
Results and discussion
Molecular design and synthesis of folic acid derivatives
We have designed and synthesized folic acid derivatives 1a–d as
shown in Chart 1.12 Thermotropic liquid crystallinity for folic
acids has been induced by introducing lipophilic moieties. The
2-(3,4-dialkoxyphenyl)ethyl moieties were introduced onto the
glutamic acid part of folic acid. Phenethyl moieties instead of a
benzyl counterpart were chosen to increase the side-chain
flexibility, which was suitable for the induction of meso-
morphic behavior. We synthesized 2-(3,4-dialkoxyphenyl)ethyl
alcohols 4 starting from ethyl 3,4-dihydroxyphenylacetate (2)
by etherification followed by the reduction of the correspond-
ing ester 3 as shown in Scheme 1. Hexyloxy-, undecyloxy-,
tetradecyloxy-, and octadecyloxy-substituted compounds 1a–d
were prepared to examine the effects of the length of the alkyl
chains on the thermal properties.
We also synthesized racemic compounds DL-1b and DL-1d
starting from DL-glutamic acid to study the effects of the
chirality of the glutamic acid part on the liquid crystallinity of
1a–d. Sodium folate showed lyotropic cholesteric phases in
aqueous media.9 The induction for the cholesteric structure was
based on the chirality of the glutamic acid.
Thermotropic liquid crystallinity and phase transition behavior of
the folic acid derivatives
Folic acid derivatives 1a–d exhibit thermotropic liquid-crystal-
line behavior. The phase transition temperatures as well as the
phase transition enthalpy changes of 1a–d determined using a
differential scanning calorimeter (DSC) on heating are sum-
marized in Table 2. It is noteworthy that the phase behavior of
1a–d is greatly dependent on the length of the alkyl chains.
Folic acid derivative 1d with 2-[3,4-bis(octadecyloxy)phenyl]-
ethyl groups forms discotic phases. Three endothermic peaks at
62, 207, and 223 uC are observed in a DSC thermogram of 1d.
The enthalpy changes of these transitions are 81, 5, and 8
kJ mol21, respectively. Polarizing microscope observation
shows that these peaks are attributed to the mesophase–
mesophase transitions and the mesophase–isotropic transition.
Similar liquid-crystalline behavior is observed for compound 1c
which has tetradecyl chains. On the other hand, for 1a and 1b,
oily streak textures, which are characteristic of smectic
phases,18 are seen over wide temperature ranges up to about
240 uC. The enthalpy changes of the smectic–isotropic transi-
tions of 1a,b are about 35 kJ mol21. The representative texture
of 1b observed by a polarizing microscope at 200 uC is shown in
Fig. 2. Similar textures are also seen in 1a. For compound 1a,
neither exothermic crystallization nor glass transition behavior
is seen on cooling below 250 uC on DSC measurement. The
Generally, direct esterification13 or alkylation14 of folic acid
to give a,c-difunctionalized folate derivatives is not easy
because of their insolubility in most organic solvents.
Furthermore, the formation of inseparable complex mixtures
containing a-conjugate, c-conjugate, and the desired a,c-
conjugate is
a serious problem. Practical regioselective
introduction of functional groups into folic acid15 was achieved
by amidations of pteroic acid derivatives{ with the functiona-
lized glutamic acid derivatives. As a key step for an efficient
synthesis of the target molecule 1, we selected a condensation
reaction of N10-(trifluoroacetyl)pteroic acid (7)16 with a,c-
bis[2-(3,4-dialkoxyphenyl)ethyl] L-glutamate 6 by a mixed
anhydride method.15a The synthetic procedure for the pre-
paration of 1a–d is shown in Scheme 2. The isolated yields are
summarized in Table 1.
Initially, alcohols 4 were condensed with N-benzyloxycarbonyl-
L-glutamic acid to give the corresponding N-benzyloxycarbonyl-
L-glutamates
5 by using 1-ethyl-3-(3-dimethylaminopropyl)
{Pteroic acid~p-[(2-amino-4-hydroxypteridin-6-ylmethyl)amino]ben-
zoic acid.
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Scheme 2 Synthesis of folic acid derivatives 1. Reagents and conditions: i) compound 4 (2.1 mol), EDC (2.2 mol), DMAP (0.2 mol), CH2Cl2, rt, 1 d;
ii) 10% Pd/C, H2, EtOAc–EtOH, 50 uC, 3 h; iii) isobutyl chloroformate (1.1 mol), Et3N (1.2 mol), DMF, rt, 1 h; iv) THF–DMF, 40 uC, 4 d, dark.
melting temperature of the chiral compound of 1b is lower by
8 uC than that of the racemic compound of DL-1b. For the
isotropization temperatures, we observe no differences between
the chiral and racemic compounds.
X-Ray diffraction measurements were carried out to
examine the phase structures of 1a–d. These results are
shown in Fig. 3. For smectic liquid-crystalline 1a and 1b,
only one sharp peak and a broad halo are observed at 25 uC
(Fig. 3, (a) and (b)). These diffraction patterns also support the
formation of the smectic phases. The layer spacings of the
Table 2 Thermal behavior of folic acid derivative 1
˚
smectic phases for 1a and 1b are 37.8 and 41.9 A, respectively.
The structures for 1a and 1b could be induced by the ribbon-
like aggregation of the pterin ring as shown in Fig. 1 (A). In
contrast, the X-ray diffraction pattern of 1d at 25 uC shows the
Compound
n
Phase transition behaviora
S
1a
6
238
(37)
235
(33)
235
(34)
232
(9)
223
(8)
225
(11)
Iso
Iso
Iso
Iso
Iso
Iso
formation of an ordered discotic hexagonal columnar (Dho
)
1b
11
Cr
213
(10)
25
(12)
36
(40)
62
(81)
63
S
DL-1b
1c
Cr
S
14
18
Dho
Dho
Dho
Dhd
Dhd
Dhd
226
(9)
207
(5)
NC
NC
NC
1d
DL-1d
207
(6)
(84)
aTransition temperatures (uC) and enthalpy changes of transitions
(kJ mol21, in parentheses). Cr: crystalline: S: semectic; Dho: ordered
discotic hexagonal columnar; Dhd: disordered discotic hexagonal
columnar; NC: nematic columnar; Iso: isotropic.
Fig. 3 X-Ray diffraction patterns of folic acid derivatives 1: (a) 1a at
25 uC; (b) 1b at 25 uC; (c) 1d at 25 uC; (d) 1d at 100 uC.
Fig. 2 Polarized photomicrograph of 1b at 200 uC.
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Fig. 4 Self-assembled smectic (A) and discotic (B) structures of folic acid derivatives 1b and 1d.
phase (Fig. 3, (c)). For example, the diffraction peaks at 50.5,
˚
29.2, and 25.3 A are attributed to the (100), (110), and (200)
lattices of the hexagonal packing, respectively. In the wide-
is consistent with the results of the X-ray diffraction. The
generation of the smectic and discotic phases of 1b and 1d is
attributed to the formation of hydrogen-bonded ribbon- and
disk-like self-assembled structures as shown in Fig. 4.
˚
angle area, a sharp peak at 4.1 A due to the distance between
˚
disks, and a broad halo at 4.2 A resulting from the disorder of
Atomic force microscopy (AFM) is a useful method for the
observation of two-dimensional molecular assemblies on
surfaces. For example, hydrogen-bonded materials on sub-
strates have been examined by this method.21 Self-assembled
structures of 1b and 1d in thin film states on a silicon substrate
were examined by AFM. The surface images of 1b and 1d are
shown in Fig. 5. For compound 1b, layer structures are
observed. The average distance of the periodical strands for 1b
the aliphatic chains, are observed. At 100 uC (Fig. 3, (d)), the
˚
peaks at 50.6, 29.2, and 25.3 A correspond to the (100), (110),
and (200) lattices, respectively. A diffused halo is also observed
˚
at 4.3 A. This pattern is characteristic of a disordered discotic
hexagonal columnar phase (Dhd). The disappearance of the
peaks due to the (110) and (200) lattices at 210 uC indicates that
1d shows a nematic columnar (NC) phase from 207 to 223 uC.19
For hexagonal columnar phases, the lattice constant reflects the
diameter of the column.20 Thus, the diameters of the self-
assembled discotic aggregate of 1d at 25 and 100 uC are 58.3
˚
˚
is 50 A, which is wider than the layer spacing (41.9 A) of the
smectic phases determined by X-ray diffraction. The average
distances may be based on the ribbon-like aggregated structure
as shown in Fig. 4 (A). In contrast, compound 1d, which forms
a disk-like aggregated structure in the bulk liquid-crystalline
state, exhibits no stripe image on the surface.
˚
and 58.4 A, respectively. The relationships between the layer
spacings and the self-assembled structures of 1b and 1d have
been examined by molecular modeling. One of the most
plausible layer structures of 1b is shown in Fig. 4 (A). The layer
˚
spacing can be estimated to be about 45 A, which is similar to
the spacing observed by X-ray diffraction measurement of 1b.
For compound 1d, the diameter of the discotic aggregate can
The difference between the ribbon- and disk-like hydrogen-
bonded structures of 1 has been examined by infrared (IR)
spectroscopy. The IR spectra of the samples of 1a, 1b, and 1d at
room temperature are shown in Fig. 6. The peak patterns are
dependent on the liquid-crystalline phase structures. In the case
˚
be arranged to be 60 A as shown in Fig. 4 (B). The distance
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were also observed for guanosine derivatives by Gottarelli10
and Sessler,11 respectively. The enthalpy difference between the
smectic–isotropic transition of 1a,b (33–37 kJ mol21) and the
discotic–isotropic transition of 1c,d (8–11 kJ mol21) listed in
Table 2 is due to the difference of ribbon- and disk-like
aggregation patterns.
Complexation of the folic acid derivatives with alkali metal
triflates
We have succeeded in inducing a phase change from smectic to
hexagonal columnar (Colh) phase by the addition of alkali
metal salts to 1b. For the metal salts, we selected sodium triflate
(NaOTf) due to the high co-solubility with organic molecules in
organic solvents. The phase diagram of 1b with NaOTf is
shown in Fig. 7. Initially, the isotropization temperatures
decrease drastically from 235 uC to 179 uC with increase of the
molar ratio of NaOTf : 1b from 0 : 1 to 0.3 : 1 in the mixtures.
Further addition of NaOTf results in the increase of the
isotropization temperatures. Fan-like textures characteristic of
the Colh phases are observed for the mixtures containing
NaOTf more than 0.5 mol. A polarized photomicrograph of
the mixture of the NaOTf and 1b in the ratio of 1.8 : 1 (mol/
mol) at 100 uC is shown in Fig. 8. The addition of the salt may
generate ion–dipolar interactions between the pterin ring and
the metal cation, resulting in the change from ribbon-like
aggregate to the disk-like tetramer. To our knowledge, the
induction of structural changes of specific hydrogen-bonded
patterns leading to liquid-crystalline phase changes has not yet
been reported, although the formation of the hexagonal
columnar mesophases by the addition of metal salts was
Fig. 5 AFM images of 1b (A) and 1d (B) on silicon surfaces.
of smectic compounds 1a and 1b, the peaks corresponding to
the N–H stretching appear at 3351 and 3341 cm21, respec-
tively. However, for discotic compound 1d, the peaks are split
into 3304 and 3251 cm21. These two patterns of the spectra can
be attributed to the ribbon- and disk-like hydrogen-bonded
structures for 1a,b and 1c,d, respectively, shown in Figs. 1 and
4. Similar hydrogen-bonded ribbon- and disk-like structures
Fig. 7 Isotropization temperatures of the complexes of NaOTf and 1b.
S: smectic; Colh: hexagonal columnar; Iso: isotropic.
Fig. 6 Infrared spectra of folic acid derivatives 1 at room temperature
on KBr: (a) 1a; (b) 1b; (c) 1d.
Fig. 8 Polarized photomicrograph of NaOTf : 1b~1.8 : 1 at 100 uC.
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Fig. 9 Isotropization temperatures of the complexes of NaOTf and 1a.
S: smectic; M: mesomorphic; Iso: isotropic.
studied.22 The addition of more than 2.5 mol of NaOTf to 1b
induces the phase separation of the sodium salt from the
mixture.
We mixed NaOTf with 1a which has hexyl chains. The
isotropization temperatures of the mixtures are shown in
Fig. 9. The addition of 0.25 mol of NaOTf to 1a results in a
decrease of the isotropization temperatures from 238 uC to
172 uC. The formation of a Colh phase is not observed for the
mixtures. Only mesomorphic sandy textures are seen for all of
the mixtures. For the induction of the Colh phases for
compounds 1 by the complexation with the metal salts, the
length of the alkyl chains should be appropriate to form a
stable outer region in the column.
For alkali metal folates, the sodium cation is more suitable
for the formation of octamers than the potassium cation.9 On
the other hand, two guanine tetramers effectively bind
potassium23 and lead(II)24 to form octamers. To examine the
effects of the cation, we prepared mixtures of LiOTf and KOTf
with 1b. The phase behaviors of the mixtures as a function of
the molar ratio are similar to that of the mixtures containing
NaOTf. The columnar phases are also induced by the addition
of the potassium and lithium salts of 1b. In the case of 1a, the
addition of these salts leads to phase destabilization; none of
the columnar phases are induced.
Fig. 10 X-Ray diffraction patterns of the sodium salts complexes of 1b
(A) and 1a (B).
X-Ray diffraction measurements have been performed to
examine the change of the self-assembled structures of the folic
acid derivatives by the addition of alkali metal triflates. The
diffraction patterns of the sodium salt complexes of 1b and 1a
are shown in Fig. 10 (A) and (B), respectively. As shown in
˚
Fig. 10 (A), the diffraction at 41.9 A becomes weaker on the
addition of 0.25 mol of the sodium salt. The diffraction peaks
attributable to the (110) lattice of the columnar mesophases are
observed for compound 1b containing 1.0 and 1.8 mol of the
sodium salt. These patterns are characteristic of the disordered
Colh phases. For the equimolar mixture of 1a, the intensity of
˚
the diffraction at 38.8 A is smaller than that of 1a. None of the
peaks corresponding to the (110) lattice appear. The addition
of sodium salt to 1a induces only destabilization of the
mesophases. The smectic–columnar phase change is only
observed for compound 1b. An IR spectroscopic study for
the mixtures of 1b with the sodium salt was carried out to
examine the hydrogen-bonded structural change from ribbon
to disk. Fig. 11 shows the results for the mixtures of 1b with
0.25 (b) and 1.2 (c) mol of the salts as well as the single
component of 1b (a). The peak pattern in Fig. 11(c) is similar to
that of 1d shown in Fig. 6(c) exhibiting the Dh phase. The result
indicates that the change of the hydrogen-bonded structures
from ribbon to disk is induced for 1b by the addition of 1.2 mol
of the sodium salt. It seems that the spectral features of 1b with
0.25 mol of NaOTf in Fig. 11(b) are between those in Fig. 11(a)
and (c).
Fig. 11 Infrared spectra of 1b and the sodium triflate complexes of 1b
at room temperature on KBr: (a) 1b; (b) NaOTf : 1b~0.25 : 1; (c)
NaOTf : 1b~1.2 : 1.
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Thermotropic behavior of a pteroylaspartate
Unless otherwise noted, all of the reactions were carried out
under an argon atmosphere in a dry solvent purchased from
Kanto Chemicals. Completion of the reactions was monitored
by thin-layer chromatography using 0.25 mm E. Merck silica
gel plates (Silica Gel F254), visualized under UV light and/or by
dipping the plates in an ethanolic sodium phosphomolybdate
followed by heating. Silica gel from Kanto Chemicals (Silica
Gel 60, spherical, 40–50 mm) was used for flash column
chromatography. Recycling preparative GPC was carried out
using a Japan Analytical Industry LC-908 chromatograph.
Measurements of melting points and phase transition tem-
peratures and determinations of liquid-crystalline phases were
carried out with an Olympus BH-2 optical polarizing micro-
scope equipped with a Mettler FP82 HT hot-stage. Thermal
characterization was conducted with a Mettler DSC 30 system
(scanning rate 10 uC min21). IR measurements were conducted
on a JASCO FT/IR-8900m in KBr unless otherwise noted.
NMR spectra were measured in a CDCl3 solution unless
otherwise noted. 1H and 13C NMR spectra were recorded on a
JEOL JNM-270 and a JEOL JNM-LA400. 19F NMR spectra
were recorded on a Varian Mercury-300 at 282 MHz. Chemical
shifts of 1H, 13C, and 19F NMR signals were quoted to internal
standard Me4Si (d~0.00), CDCl3 (d~77.00), and CFCl3
(d~0.00), respectively, and expressed as chemical shifts in
ppm (d), multiplicity, coupling constant (Hz), and relative
intensity. Mass spectra were recorded on a Shimadzu GC/MS
QP-5000 spectrometer (70 eV). Matrix associated laser deso-
rption ionization–time of flight mass spectra (MALDI-TOF
MS) were taken on a PerSeptive Biosystems Voyager-DE2
STR spectrometer. Elemental analyses were carried out on a
Perkin-Elmer CHNS/O 2400 apparatus. X-Ray diffraction
measurements were carried out on a Rigaku X-ray Rad 2B
system with a heating stage using Ni-filtered CuKa radiation.
The liquid-crystalline structures of 1a–d depend on the length
of the alkyl chains. The effect of the glutamic acid moiety on
the liquid crystallinity is also of interest. Our synthetic
procedure for
1 enables us to introduce a variety of
functionalized amino acids to the pteroic acid moiety. We
synthesized pteroylaspartate 11 with octadecyl chains. The
synthetic route to 11 is shown in Scheme 3. Compound 11
shows thermotropic discotic liquid crystallinity from room
temperature to 223 uC. The transition temperatures and phase
structures are as follows: Dho 64 Dhd 193 NC 223 Iso. The Dhd
NC transition temperature of 11 is lower by 14 uC than that of
1d, which suggests that the glutamic acid moiety is preferred for
–
the stabilization of the hexagonal columnar structure.
Synthesis of ethyl 3,4-dihydroxyphenylacetate (2). A deaer-
ated ethanolic solution (300 mL) of 3,4-dihydroxyacetic acid
(20 g, 119 mmol) and conc. H2SO4 (1 mL) was heated to reflux
with stirring under an argon atmosphere for 4 h. The reaction
mixture was then cooled and the solvent was evaporated under
reduced pressure. The residue was dissolved in EtOAc
(300 mL) and poured into H2O (300 mL). The organic phase
was separated and the aqueous phase was extracted with
EtOAc three times (total 500 mL). The combined organic
extracts were washed with successive, 5% aq. NaHCO3
(300 mL) and sat. aq. NaCl (300 mL). The resulting extracts
were dried over anhydrous magnesium sulfate, filtered through
a pad of Celite, and concentrated in vacuo to give 2 in a
quantitative yield as pale yellow solids. Further purification
was not necessary for the next step. Rf~0.47 (hexane–
EtOAc~1 : 1). IR (neat) 3394, 2984, 1701, 1609, 1522, 1449,
Scheme 3 Synthesis of pteroyl-L-aspartate 11.
Conclusions
We have prepared thermotropic liquid-crystalline folic acid
derivatives 1a–d by introducing long alkyl chains. Compounds
1a,b having shorter alkyl chains show smectic phases, while
discotic phases are observed for compounds 1c,d having longer
alkyl chains. We have found that the smectic phase exhibited by
1b is changed to the hexagonal columnar phase when more
than 0.5 mol of alkali metal salts such as LiOTf, NaOTf, and
KOTf are added. The change of the hydrogen-bonded
structures from ribbon to disk induced by the ion–dipolar
interaction between the pterin ring and the metal cation is a key
for this process. However, this phase change is not induced for
1a. The appropriate length of the alkyl chain is necessary to
induce such structural change. These supramolecular materials
reported here have great potential for dynamically functional
materials responsive to external stimuli and to the change of
atmosphere if we can control the shapes and interactions of
molecules.
1374, 1287, 1030, 970, 850, 798 cm21 1H NMR (400 MHz)
;
d~6.79 (s, 1 H), 6.78 (d, J~8 Hz, 1 H), 6.69 (d, J~8 Hz, 1 H),
5.58 (s, 1 H), 5.36 (s, 1 H), 4.16 (q, J~7 Hz, 2 H), 3.50 (s, 2 H),
1.29 (t, J~7 Hz, 3 H); 13C NMR (100 MHz) d~173.4, 143.8,
143.1, 125.9, 121.5, 116.2, 115.3, 61.3, 40.6, 14.0; MS m/z (rel
intensity) 197 (Mzz1, 3), 196 (Mz, 22), 167 (5), 149 (15), 124
(12), 123 (100), 105 (11), 97 (15), 91 (12), 88 (13), 73 (32), 70
(77), 64 (30). Found: C, 60.20; H, 6.41%. Calcd for C10H12O4:
C, 61.22; H, 6.16%.
General procedure for the preparation of ethyl 3,4-
dialkoxyphenylacetate (3)
Experimental section
A
DMF (200 mL) suspension of 2 (19.6 g, 0.100 mol),
1-bromoalkane (0.22 mol), and K2CO3 (54 g, 0.40 mol) in a
round-bottomed flask (1 L) equipped with a stirring bar was
deaerated under reduced pressure, and the flask was filled with
argon. The deaeration was repeated three times to remove
oxygen in the flask, thoroughly. After the resulting mixture was
heated at 80 uC for 1 day with vigorous stirring, the mixture
General techniques
All reagents of the highest commercial quality and solvents
were purchased from Aldrich Chemical, Kanto Chemicals,
Tokyo Kasei, or Wako Pure Chemicals, and were used as
received. 10% Pd/C was purchased from Kojima Chemicals.
J. Mater. Chem., 2001, 11, 2875–2886
2881

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was poured into a mixture of warm water and EtOAc (40 uC,
500 mL of each). The organic phase was separated, and the
aqueous phase was extracted with EtOAc three times (total
500 mL). The combined organic extracts were washed with
equal-volume portions of warm water, 10% NH4Cl aq.
solution, and sat. aq. NaCl, successively. The resulting warm
organic phase was dried over MgSO4, filtered through a pad of
Celite before cooling, and concentrated under reduced
pressure. The residue was recrystallized from ethanol to give
3. The yields and the spectroscopic data are summarized as
follows.
Preparation of 2-(3,4-dialkoxyphenyl)ethanol 4: general
procedure
To a stirred suspension of lithium aluminium hydride (LAH,
3.6 g, 96 mmol) in THF (50 mL) was added a solution of 3
(80 mmol) in THF (100 mL) at 0 uC over a period of 10 min.
The mixture was stirred at room temperature for 3 h, quenched
by slow addition of PriOH (3 mL), H2O (5 mL), and 30% aq.
NaOH (5 mL) at 0 uC, successively. The resulting mixture was
stirred at room temperature for 3 h before mixing with Celite,
anhydrous MgSO4, and diethyl ether (300 mL). The insoluble
materials were filtered off through a pad of Celite by using a
suction funnel, and the filter cake was washed with diethyl ether
(50 mL, 4 times) and CH2Cl2 (50 mL, 4 times), successively.
The filtrate was concentrated under reduced pressure, and the
residue was recrystallized from hexane to give 4. The isolated
yields and spectral properties of 4 are as follows.
Ethyl 3,4-bis(hexyloxy)phenylacetate (3a). This compound
was purified by silica gel flash-column chromatography
(hexane–EtOAc~10 : 1) instead of recrystallization. Yield
79%, colorless oil; Rf~0.54 (hexane–EtOAc~5 : 1). IR (neat)
2932, 2861, 1734, 1517, 1508, 1473, 1457, 1262, 1143, 1033,
794 cm21; 1H NMR (270 MHz) d~6.77–6.93 (m, 3 H), 4.14 (q,
J~7 Hz, 2 H), 3.92–4.03 (m, 4 H), 3.52 (s, 2 H), 1.72–1.86 (m,
4 H), 1.21–1.57 (m, 12 H), 1.25 (t, J~7 Hz, 3 H), 0.90 (t,
J~6 Hz, 6 H); 13C NMR (100 MHz) d~171.8, 149.0, 148.1,
126.6, 121.4, 114.7, 113.7, 69.2, 69.1, 60.7, 40.9, 31.5, 29.2, 25.6,
22.6, 14.1, 14.0; MS m/z (rel intensity) 366 (Mzz2, 0.1), 365
(Mzz1, 1), 364 (Mz, 5), 280 (3), 197 (6), 196 (55), 168 (2), 149
(30), 123 (100), 105 (6), 77 (8), 71 (10). Found: C, 72.31; H,
10.02%. Calcd for C22H36O4: C, 72.49; H, 9.95%.
2-[3,4-Bis(hexyloxy)phenyl]ethanol (4a). This compound was
purified by flash column chromatography (hexane–
EtOAc~5 : 1) in lieu of recrystallization. Yield 100%. A
colorless oil; Rf~0.32 (hexane–EtOAc~5 : 2). IR (neat)
3363, 2931, 2861, 1590, 1516, 1472, 1426, 1387, 1260, 1233,
1
1139, 1047, 798 cm21; H NMR (270 MHz) d~6.72–6.85 (m,
3 H), 3.98 (t, J~7 Hz, 2 H), 3.96 (t, J~7 Hz, 2 H), 3.80–3.86
(m, 2 H), 2.79 (t, J~6 Hz, 2 H), 1.74–1.83 (m, 4 H), 1.27–1.46
(m, 12 H), 0.88 (t, J~7 Hz, 6 H); 13C NMR (100 MHz)
d~149.2, 147.8, 130.9, 121.1, 114.7, 114.1, 69.4, 69.2, 63.7,
38.7, 31.6, 29.3, 25.7, 22.6, 14.0; MS m/z (rel intensity) 323
(Mzz1, 3), 322 (Mz, 15), 238 (10), 154 (61), 124 (10), 123
(100), 77 (6). Found: C, 74.16; H, 10.78%. Calcd for C20H34O3:
C, 74.49; H, 10.63%.
Ethyl 3,4-bis(undecyloxy)phenylacetate (3b). Yield 91%.
Colorless solid, mp~40.5–42.4 uC; Rf~0.57 (hexane–
EtOAc~5 : 1). IR 2923, 2850, 1738, 1526, 1469, 1265, 1191,
1138, 1031, 1003, 876, 791 cm21
;
1H NMR (270 MHz)
d~6.70–6.83 (m, 3 H), 4.14 (q, J~7 Hz, 2 H), 3.91–4.03 (m,
4 H), 3.52 (s, 2 H), 1.69–1.88 (m, 4 H), 1.18–1.59 (m, 35 H), 0.88
(t, J~6 Hz, 6 H); 13C NMR (100 MHz) d~172.0, 149.1, 148.0,
126.6, 121.4, 114.8, 113.8, 69.3, 69.1, 60.7, 40.9, 31.9, 29.6, 29.4,
29.34, 29.26, 26.0, 22.7, 14.2, 14.1; MS m/z (rel intensity) 506
(Mzz2, 0.4), 505 (Mzz1, 2), 504 (Mz, 6), 350 (2), 197 (8),
196 (71), 168 (2), 135 (7), 124 (10), 123 (100), 97 (6), 83 (10), 69
(28). Found: C, 76.47; H, 11.40%. Calcd for C32H56O4: C,
76.14; H, 11.18%.
2-[3,4-Bis(undecyloxy)phenyl]ethanol (4b). Yield 92%. Color-
less solid, mp 44.8–45.2 uC; Rf~0.44 (hexane–EtOAc~5 : 2).
IR 3460, 2919, 2850, 1518, 1471, 1428, 1261, 1232, 1138, 1026,
807, 720 cm21 1H NMR (270 MHz) d~6.72–6.85 (m, 3 H),
;
3.98 (t, J~7 Hz, 2 H), 3.97 (t, J~7 Hz, 2 H), 3.79–3.86 (m, 2 H),
2.79 (t, J~6 Hz, 2 H), 1.74–1.83 (m, 4 H), 1.27–1.46 (m, 32 H),
0.88 (t, J~7 Hz, 6 H); 13C NMR (100 MHz) d~149.2, 147.7,
131.0, 121.1, 114.7, 114.1, 69.4, 69.2, 63.7, 38.7, 31.9, 29.6, 29.4,
29.34, 29.30, 26.0, 22.7, 14.1; MS m/z (rel intensity) 464 (Mzz2,
2), 463 (Mzz1, 10), 462 (Mz, 32), 308 (9), 155 (8), 154 (94), 124
(11), 123 (100), 97 (8), 83 (11), 71 (15), 69 (27). Found: C, 78.18;
H, 11.69%. Calcd for C30H54O3: C, 77.87; H, 11.76%.
Ethyl 3,4-bis(tetradecyloxy)phenylacetate (3c). Yield 75%.
Colorless solid, mp~51.1–51.9 uC; Rf~0.59 (hexane–
EtOAc~5 : 1). IR 2954, 2919, 2849, 1739, 1525, 1469, 1331,
;
1265, 1189, 1138, 1033, 722 cm21 1H NMR (270 MHz)
d~6.78–6.91 (m, 3 H), 4.14 (q, J~7 Hz, 2 H), 3.96–4.10 (m,
4 H), 3.52 (s, 2 H), 1.64–1.91 (m, 4 H), 1.03–1.61 (m, 47 H), 0.88
(t, J~8 Hz, 6 H); 13C NMR (100 MHz) d~171.9, 149.0, 148.1,
126.6, 121.4, 114.8, 113.8, 69.2, 69.1, 60.7, 40.9, 31.9, 29.7, 29.6,
29.42, 29.36, 29.26, 26.0, 22.7, 14.2, 14.1; MS m/z (rel intensity)
591 (Mzz2, 2), 590 (Mzz1, 8), 589 (Mz, 18), 515 (0.4), 392
(4), 197 (12), 196 (100), 163 (3), 150 (2), 135 (5), 123 (77), 97 (8),
83 (15), 71 (20), 69 (33). Found: C, 77.63; H, 11.76%. Calcd for
C38H68O4: C, 77.50; H, 11.64%.
2-[3,4-Bis(tetradecyloxy)phenyl]ethanol (4c). Yield 100%.
Colorless solid, mp 56.7–57.4 uC; Rf~0.50 (hexane–
EtOAc~5 : 2). IR 3447, 2918, 2849, 1519, 1472, 1263, 1233,
1138, 1022, 809, 720 cm21; 1H NMR (270 MHz) d~6.68–6.87
(m, 3 H), 3.89–4.02 (m, 4 H), 3.77–3.99 (m, 2 H), 2.79 (t,
J~6 Hz, 2 H), 1.69–1.90 (m, 4 H), 1.10–1.59 (m, 45 H), 0.88 (t,
J~7 Hz, 6 H); 13C NMR (100 MHz) d~149.2, 147.8, 131.0,
121.1, 114.7, 114.1, 69.4, 69.2, 63.7, 38.7, 31.9, 29.7, 29.6, 29.43,
29.36, 29.31, 26.0, 22.7, 14.1; MS m/z (rel intensity) 549
(Mzz3, 2), 548 (Mzz2, 10), 547 (Mzz1, 12), 350 (6), 154
(88), 152 (12), 137 (13), 124 (15), 123 (100), 107 (3), 97 (12), 85
(11), 83 (21), 71 (27), 70 (11), 69 (44). Found: C, 79.56; H,
12.34%. Calcd for C36H66O3: C, 79.06; H, 12.16%.
Ethyl 3,4-bis(octadecyloxy)phenylacetate (3d). Yield 86%.
Colorless solid, mp~53.9–54.5 uC; Rf~0.59 (hexane–
EtOAc~5 : 1). IR 2956, 2918, 2850, 1735, 1518, 1468, 1431,
;
1270, 1235, 1143, 1034, 721 cm21 1H NMR (400 MHz)
d~6.74–6.90 (m, 3 H), 4.14 (q, J~7 Hz, 2 H), 3.92–4.05 (m,
4 H), 3.51 (s, 2 H), 1.75–1.94 (m, 4 H), 1.15–1.57 (m, 61 H), 0.88
(t, J~7 Hz, 6 H); 13C NMR (100 MHz) d~171.9, 149.3, 148.1,
126.7, 121.5, 114.8, 113.8, 69.3, 69.2, 60.7, 40.9, 31.9, 29.70,
29.66, 29.43, 29.36, 29.26, 26.0, 22.7, 14.2, 14.1; MS m/z (rel
intensity) 703 (Mzz2, 1), 702 (Mzz1, 6), 701 (Mz, 11), 449
(4), 197 (13), 196 (100), 137 (5), 124 (12), 123 (92), 97 (17), 83
(24), 71 (30), 69 (41). Found: C, 78.93; H, 12.29%. Calcd for
C46H84O4: C, 78.80; H, 12.08%.
2-[3,4-Bis(octadecyloxy)phenyl]ethanol (4d). Yield 97%. Color-
less solid, mp 66.5–67.4 uC; Rf~0.54 (hexane–EtOAc~5 : 2). IR
3420, 2918, 2850, 1518, 1468, 1265, 1234, 1139, 1048, 806,
1
721 cm21; H NMR (270 MHz) d~6.71–6.85 (m, 3 H), 3.98 (t,
J~7 Hz, 2 H), 3.96 (t, J~7 Hz, 2 H), 3.80–3.86 (m, 2 H), 2.79 (t,
J~6 Hz, 2 H), 1.74–1.85 (m, 4 H), 1.26–1.48 (m, 60 H), 0.88
(t, J~7 Hz, 6 H); 13C NMR (100 MHz) d~149.2, 147.7, 131.0,
121.1, 114.7, 114.2, 69.4, 69.2, 63.7, 38.7, 31.9, 29.7, 29.6, 29.44,
2882
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29.36, 29.33, 26.1, 22.7, 14.1; MALDI-TOF MS (indole-3-acrylic
acid (IAA)) m/z 681.8 (MzNaz, C44H82O3 requires 681.6).
Found: C, 80.40; H, 12.59%. Calcd for C44H82O3: C, 80.18; H,
12.54%.
149.11, 149.06, 147.9, 147.8, 136.1, 130.1, 129.6, 128.4, 128.1,
128.0, 121.0, 114.6, 114.5, 113.9, 69.24, 69.17, 66.9, 66.1, 65.3,
53.3, 34.5, 31.9, 30.0, 29.7, 29.6, 29.4, 29.3, 27.4, 26.0, 22.6, 14.0;
MALDI-TOF MS (IAA) m/z 1361.9 (MzNaz, C85H143NO10
requires 1361.1). Found: C, 76.71; H, 11.05; N, 0.98%. Calcd for
C85H143NO10: C, 76.24; H, 10.76; N, 1.05%.
General method for synthesis of bis[2-(3,4-dialkoxyphenyl)ethyl]
N-benzyloxycarbonyl-L-glutamate 5
Bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl} N-benzyloxycarbo-
nyl-L-glutamate (5d). Yield 86%. Colorless solid, mp~68.8–
70.0 uC; Rf~0.69 (hexane–EtOAc~5 : 2). IR 3316, 2919, 2850,
To a mixture of 2-(3,4-dialkoxyphenyl)ethanol (4, 18 mmol),
N-benzyloxycarbonyl-L-glutamic acid (2.5 g, 8.8 mmol), and
DMAP (0.43 g, 3.5 mmol) in CH2Cl2 (80 mL), EDC (4.5 g,
24 mmol) was added portionwise at room temperature over
10 min. The reaction mixture was stirred overnight at the same
temperature, and the resulting mixture was poured into an aq.
NH4Cl solution (200 mL). The insoluble material was dissolved
in CHCl3 (300 mL), and the organic phase was separated. The
aqueous phase was extracted three times with CHCl3 (total
500 mL). The combined organic extracts were washed with sat.
aq. NH4Cl solution (200 mL) and sat. aq. NaCl solution
(200 mL). The resulting organic phase was dried over MgSO4,
filtered, and evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(eluent: hexane–EtOAc~5 : 1) to give 5.
1734, 1518, 1468, 1265, 1235, 1165, 1140, 1068, 804, 721 cm21
;
1H NMR (400 MHz) d~7.23–7.45 (m, 5 H), 6.62–6.89 (m, 6 H),
5.33 (d, J~9 Hz, 1 H), 5.10 (s, 2 H), 4.31–4.45 (m, 1 H), 4.31
(t, J~7 Hz, 2 H), 4.23 (t, J~7 Hz, 2 H), 3.85–4.08 (m, 8 H),
2.85 (t, J~7 Hz, 2 H), 2.87 (t, J~7 Hz, 2 H), 2.28–2.45 (m, 2 H),
2.10–2.25 (m, 1 H), 1.82–1.99 (m, 1 H), 1.70–1.82 (m, 8 H),
1.12–1.58 (m, 120 H), 0.88 (t, J~7 Hz, 12 H); 13C NMR
(100 MHz) d~172.5, 171.7, 155.9, 149.16, 149.11, 147.93,
147.86, 136.0, 130.1, 129.7, 128.5, 128.14, 128.06, 121.0, 114.7,
114.5, 114.0, 69.3, 69.2, 67.0, 66.2, 65.4, 53.3, 34.5, 31.9, 29.7,
29.6, 29.4, 29.3, 27.5, 26.0, 22.7, 14.1; MALDI-TOF MS (IAA)
m/z 1586.5 (Mz1zNaz, C101H175NO10 requires 1586.3).
Found: C, 77.88; H, 11.47; N, 1.03%. Calcd for C101H175NO10:
C, 77.59; H, 11.28; N, 0.90%.
Bis{2-[3,4-bis(hexyloxy)phenyl]ethyl} N-benzyloxycarbonyl-
L-glutamate (5a). Yield 70%. Colorless solid, mp 41.7–
42.5 uC; Rf~0.53 (hexane–EtOAc~5 : 2). IR 3326, 2956,
2931, 2859, 1729, 1687, 1590, 1519, 1468, 1428, 1393, 1262,
Bis{2-[3,4-bis(undecyloxy)phenyl]ethyl} N-benzyloxycarbonyl-
DL-glutamate (DL-5b). Yield 74%. Spectroscopic data of DL-5b
were identical to those of 5b.
1
1236, 1140, 1068, 1048, 802, 732 cm21; H NMR (270 MHz)
d~7.26–7.41 (m, 5 H), 6.65–6.83 (m, 6 H), 5.35 (d, J~8 Hz, 1
H), 5.09 (s, 2 H), 4.32–4.43 (m, 1 H), 4.13 (t, J~7 Hz, 2 H),
4.31 (t, J~7 Hz, 2 H), 3.89–4.01 (m, 8 H), 2.77–2.91 (m, 4 H),
2.22–2.43 (m, 2 H), 2.10–2.21 (m, 1 H), 1.87–2.04 (m, 1 H),
1.71–1.87 (m, 8 H), 1.20–1.57 (m, 24 H), 1.90 (t, J~6 Hz, 12
H); 13C NMR (100 MHz) d~172.6, 171.7, 155.8, 149.13,
149.07, 147.9, 147.8, 136.0, 130.1, 129.7, 128.5, 128.2, 128.1,
121.0, 114.6, 114.5, 113.9, 69.3, 69.2, 67.0, 66.2, 65.4, 53.3,
34.54, 34.48, 31.6, 30.0, 29.3, 27.5, 25.7, 22.6, 14.0; MALDI-
TOF MS (IAA) m/z 912.9 (MzNaz, C53H79NO10 requires
912.6). Found: C, 71.83; H, 9.12; N, 1.60%. Calcd for
C53H79NO10: C, 71.51; H, 8.94; N, 1.57%.
Bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl} N-benzyloxycarbonyl-
DL-glutamate (DL-5d). Yield 85%. Spectroscopic data of DL-5d
were the same as those of 5d.
Representative procedure for the preparation of bis{2-[3,4-
bis(undecyloxy)phenyl]ethyl} L-glutamate (6b)
A suspension of 5b (5.0 g, 4.3 mmol) and 10% Pd/C (1.0 g) in
EtOAc (60 mL) and EtOH (40 mL) was vigorously stirred for
3 h at 50 uC under a hydrogen atmosphere with a slightly
positive pressure. The resulting mixture was filtered through a
pad of Celite/Wakogel C-100, and the filtrate was concentrated
in vacuo. Purification of the residue by flash silica gel column
chromatography (eluent: CH2Cl2–EtOAc~10 : 1, Rf~0.43)
afforded 6b as a colorless solid in a yield of 56% (2.5 g,
2.4 mmol), mp~45.2–45.9 uC. IR 3386, 3322, 2921, 2847, 1726,
1606, 1590, 1516, 1472, 1428, 1391, 1330, 1266, 1228, 1182,
1142, 1070, 1028, 998, 980, 945, 857, 814, 721 cm21; 1H NMR
(400 MHz) d~6.70–6.81 (m, 6 H), 4.23–4.31 (m, 4 H), 3.94–
3.98 (m, 8 H), 3.42 (dd, J~5, 8 Hz, 1 H), 2.83–2.90 (m, 4 H),
2.43 (t, J~8 Hz, 2 H), 2.00–2.07 (m, 1 H), 1.76–1.84 (m, 9 H),
1.26–1.46 (m, 64 H), 0.88 (t, J~7 Hz, 12 H); 13C NMR
(100 MHz) d~175.5, 173.1, 149.12, 149.08, 147.89, 147.83,
130.2, 129.9, 121.0, 114.7, 114.6, 114.0, 69.34, 69.26, 65.6, 65.2,
53.7, 34.6, 31.9, 30.5, 29.6, 29.5, 29.4, 29.3, 26.0, 22.7, 14.1;
MALDI-TOF MAS (IAA): m/z 1037.3 (Mz1, C65H113NO8
requires 1036.8). Found: C, 75.00; H, 11.14; N, 1.40%. Calcd
for C65H113NO8: C, 75.31; H, 10.99; N, 1.35%.
Bis{2-[3,4-bis(undecyloxy)phenyl]ethyl} N-benzyloxycarbonyl-
L-glutamate (5b). Yield 80%. Colorless solid, mp~49.3–
50.0 uC; Rf~0.62 (hexane–EtOAc~5 : 2). IR 3317, 2922,
2852, 1732, 1687, 1540, 1520, 1467, 1264, 1234, 1173, 1140,
1057, 999, 802 cm21 1H NMR (400 MHz) d~7.26–7.38 (m,
;
5 H), 6.64–6.82 (m, 6 H), 5.36 (d, J~9 Hz, 1 H), 5.08 (s, 2 H),
4.33–4.43 (m, 1 H), 4.30 (t, J~7 Hz, 2 H), 4.22 (t, J~7 Hz,
2 H), 3.82–4.00 (m, 8 H), 2.84 (t, J~7 Hz, 2 H), 2.82 (t,
J~7 Hz, 2 H), 2.25–2.42 (m, 2 H), 2.08–2.21 (m, 1 H), 1.86–
1.98 (m, 1 H), 1.72–1.85 (m, 8 H), 1.08–1.26 (m, 64 H), 0.86 (t,
J~7 Hz, 12 H); 13C NMR (100 MHz) d~172.5, 171.6, 155.8,
149.1, 149.0, 147.86, 147.78, 136.1, 130.1, 129.6, 128.4, 128.1,
128.0, 120.1, 114.6, 114.5, 113.9, 69.22, 69.16, 66.9, 66.1,
65.3, 53.3, 34.5, 31.8, 30.0, 29.6, 29.4, 29.3, 27.4, 26.0, 22.6,
14.0; MALDI-TOF MS (IAA) m/z 1193.7 (Mz1zNaz,
C73H119NO10 requires 1193.9). Found: C, 74.82; H, 10.43; N,
1.39%. Calcd for C73H119NO10: C, 74.89; H, 10.25; N, 1.20%.
Bis{2-[3,4-bis(tetradecyloxy)phenyl]ethyl} N-benzyloxycarbonyl-
L-glutamate (5c). Yield 80%. Colorless solid, mp~59.7–60.6 uC;
Rf~0.66 (hexane–EtOAc~5 : 2). IR 3319, 2920, 2851, 1732, 1686,
1519, 1468, 1265, 1235, 1171, 1139, 1055, 794, 721 cm21; 1H NMR
(400 MHz) d~7.26–7.40 (m, 5 H), 6.62–6.83 (m, 6 H), 5.37 (d,
J~8 Hz, 1 H), 5.10 (s, 2 H), 4.34–4.43 (m, 1 H), 4.31 (t, J~7 Hz,
2 H), 4.23 (t, J~7 Hz, 2 H), 3.89–4.00 (m, 8 H), 2.87 (t, J~7 Hz,
2 H),2.84 (t,J~7 Hz, 2 H), 2.26–2.44 (m, 2 H), 2.09–2.19 (m, 1 H),
1.86–1.98 (m, 1 H), 1.73–1.82 (m, 8 H), 1.19–1.53 (m, 88 H), 0.88
(t, J~7 Hz, 12 H); 13C NMR (100 MHz) d~172.5, 171.6, 155.8,
Bis{2-[3,4-bis(hexyloxy)phenyl]ethyl} L-glutamate (6a). Com-
pound 6a was prepared in 66% yield from 5a. A pale yellow
viscous oil; Rf~0.39 (CHCl3–MeOH~10 : 1). IR 3210, 2932,
2861, 1740, 1699, 1516, 1469, 1428, 1262, 1234, 1140, 1046, 1019,
804, 726 cm21; 1H NMR (270 MHz) d~6.70–6.82 (m, 6 H), 4.29
(t, J~7 Hz, 2 H), 4.25 (t, J~7 Hz, 2 H), 3.97 (t, J~7 Hz, 4 H),
3.96 (t, J~7 Hz, 4 H), 3.42 (dd, J~5, 8 Hz, 1 H), 2.82–2.89 (m,
4 H), 2.42 (t, J~7 Hz, 2 H), 1.97–2.10 (m, 1 H), 1.74–1.86 (m, 9
H), 1.26–1.58 (m, 26 H), 0.88 (t, J~7 Hz, 12 H); 13C NMR
(100 MHz) d~175.0, 172.6, 148.80, 148.76, 147.6, 147.5, 130.0,
J. Mater. Chem., 2001, 11, 2875–2886
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129.7, 120.7, 114.35, 114.27, 113.6, 68.9, 68.8, 65.2, 64.8, 53.3,
34.3, 31.3, 29.0, 25.4, 22.3, 13.7; MALDI-TOF MS (IAA) m/z
756.6 (Mz1, C45H73NO8 requires 756.5). Found: C, 71.54; H,
9.98%. Calcd for C45H73NO8: C, 71.49; H, 9.73%.
solid in a yield of 40%. Phase transition temperature (DSC on
heating): Cr 213 S 235 Iso. Rf~0.40 (CH2Cl2–EtOH–
benzene~13 : 1 : 1). IR 2924, 2855, 1698, 1609, 1512, 1466,
1424, 1389, 1343, 1262, 1208, 1157, 1007, 857, 799, 721 cm21
;
1H NMR (400 MHz) d~8.81 (s, 1 H), 7.87 (d, J~8 Hz, 2 H),
7.42 (d, J~8 Hz, 2 H), 6.81–6.69 (m, 6 H), 5.16 (s, 2 H), 4.77–
4.72 (m, 1 H), 4.36–4.21 (m, 4 H), 3.99–3.93 (m, 8 H), 2.88 (t,
J~7 Hz, 2 H), 2.83 (t, J~7 Hz, 2 H), 2.47–2.35 (m, 2 H), 2.26–
2.20 (m, 1 H), 2.11–2.04 (m, 1 H), 1.80–1.76 (m, 8 H), 1.43–1.24
(m, 64 H), 0.86 (t, J~7 Hz, 12 H); 19F NMR (282 MHz)
d~267.4; MALDI-TOF MS (IAA) m/z 1427.7 (Mz2,
C81H122F3N7O11 requires 1427.9). Found: C, 68.03; H, 8.58;
N, 6.87%. Calcd for C81H122F3N7O11: C, 68.18; H, 8.62; N,
6.87%.
Bis{2-[3,4-bis(tetradecyloxy)phenyl]ethyl} L-glutamate (6c.).
Synthesis of 6c was carried out in benzene instead of in
EtOAc–EtOH. Yield 16%. Colorless solid, mp~59.1–60.0 uC;
Rf~0.54 (CHCl3–MeOH~10 : 1). IR 3393, 2919, 1730, 1519,
1471, 1266, 1233, 1140, 1020, 814, 721 cm21 1H NMR
;
(400 MHz) d~6.69–6.82 (m, 6 H), 4.21–4.35 (m, 4 H), 3.90–
4.05 (m, 8 H), 3.43 (dd, J~5, 6 Hz, 1 H), 2.77–2.90 (m, 4 H),
2.43 (t, J~8 Hz, 2 H), 1.99–2.10 (m, 1 H), 1.73–1.90 (m, 9 H),
1.53 (br s, 2 H), 1.13–1.55 (m, 88 H), 0.88 (t, J~7 Hz, 12 H);
13C NMR (100 MHz) d~175.5, 173.0, 149.13, 149.10, 147.9,
147.8, 130.3, 129.9, 121.0, 114.7, 114.6, 114.0, 69.4, 69.3, 65.6,
65.2, 53.7, 34.6, 31.9, 30.5, 29.7, 29.53, 29.46, 29.36, 29.33, 26.1,
22.7, 14.1; MALDI-TOF MS (IAA) m/z 1205.5 (Mz1,
C77H137NO8 requires 1205.0). Found: C, 76.99; H, 11.69; N,
1.18%. Calcd for C77H137NO8: C, 76.75; H, 11.46; N, 1.16%.
Bis{2-[3,4-bis(hexyloxy)phenyl]ethyl} N-[N10-(trifluoroacetyl)-
pteroyl]-L-glutamate (1a). Yield 65%. Yellow mesomorphic
solid. Phase transition temperature (DSC on heating): S 238
Iso. Rf~0.58 (CHCl3–MeOH~6 : 1). IR 2932, 2860, 1717,
1
1699, 1517, 1508, 1261, 1212, 1162, 1017, 825, 802 cm21; H
NMR (400 MHz, DMSO) d~11.5 (s, 1 H), 8.83 (d, J~7 Hz, 1
H), 8.62 (s, 1 H), 7.87 (d, J~8 Hz, 2 H), 7.63 (d, J~8 Hz, 2 H),
6.59–6.91 (m, 6 H), 6.50–7.20 (br m, 2 H), 5.10 (s, 2 H), 4.39 (m,
1 H), 4.14 (t, J~7 Hz, 2 H), 4.17–4.28 (m, 2 H), 3.75–3.98 (m, 8
H), 2.71–2.82 (m, 4 H), 2.36 (t, J~7 Hz, 2 H), 1.83–2.08 (m, 2
H), 1.54–1.70 (m, 8 H), 1.17–1.50 (m, 24 H), 0.84 (t, J~5 Hz,
12 H); 19F NMR (282 MHz) d~267.4; MALDI-TOF MS
(IAA) m/z 1146.0 (M, C61H82F3N7O11 requires 1145.6). Found:
C, 63.69; H, 7.34; N, 8.55%. Calcd for C61H82F3N7O11: C,
63.91; H, 7.21; N, 8.55%.
Bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl} L-glutamate (6d).
Obtained in 61% yield from 5d. The reaction was performed
in CH2Cl2–EtOH–HCO2H (25 : 5 : 1, wt/wt/wt) for 1.5 h instead
of in benzene. Colorless solid, mp~70.5–71.1 uC; Rf~0.61
(CHCl3–MeOH~10 : 1). IR 3751, 2919, 2851, 1735, 1518,
1
1468, 1267, 1234, 1141, 1070, 1021, 808, 721 cm21; H NMR
(400 MHz) d~6.70–6.82 (m, 6 H), 4.19–4.30 (m, 4 H), 3.88–
4.03 (m, 8 H), 3.43 (dd, J~5, 6 Hz, 1 H), 2.76–2.92 (m, 4 H),
2.43 (t, J~7 Hz, 2 H), 1.98–2.10 (m, 1 H), 1.73–1.82 (m, 9 H),
1.55 (br s, 2 H), 1.11–1.53 (m, 120 H), 0.88 (t, J~7 Hz, 12 H);
13C NMR (100 MHz) d~172.5, 172.4, 149.2, 149.1, 148.0,
147.8, 129.9, 129.3, 121.0, 114.6, 114.5, 113.9, 69.30, 69.26,
65.6, 64.9, 34.5, 34.3, 31.9, 29.9, 29.5, 29.4, 26.3, 26.1, 22.7,
14.1; MALDI-TOF MS (IAA) m/z 1430.0 (Mz2, C93H169NO8
requires 1430.3). Found: C, 75.82; H, 11.83; N, 1.19%. Calcd
for C93H169NO8?0.5CHCl3: C, 75.42; H, 11.47; N, 0.94%.
Bis{2-[3,4-bis(tetradecyloxy)phenyl]ethyl}N-[N10-(trifluoroacetyl)-
pteroyl]-L-glutamate (1c). Yield 42%. Yellow waxy solid. Phase
transition temperature (DSC on heating): Dho 36 Dhd 226 NC
232 Iso. Rf~0.59 (CHCl3–MeOH~6 : 1). IR 3421, 2922, 2853,
1734, 1717, 1700, 1534, 1517, 1508, 1457, 1264, 1212, 1161, 854,
802 cm21; 1H NMR (400 MHz) d~8.81 (s, 1 H), 7.77–7.92 (m,
2 H), 7.32–7.50 (m, 2 H), 6.60–6.75 (m, 6 H), 5.17 (s, 2 H), 4.69–
4.78 (m, 1 H), 4.17–4.45 (m, 4 H), 3.88–4.02 (m, 8 H), 2.88 (t,
J~7 Hz, 2 H), 2.83 (t, J~6 Hz, 2 H), 2.27–2.55 (m, 2 H), 2.02–
2.18 (m, 1 H), 2.20–2.31 (m, 1 H), 1.69–1.80 (m, 8 H), 0.97–1.46
(m, 88 H), 0.87 (t, J~6 Hz, 12 H); 19F NMR (282 MHz)
d~267.5; MALDI-TOF MS (IAA) m/z 1595.1 (Mz1,
C93H82F3N7O11 requires 1595.1). Found: C, 70.01; H, 9.39;
N, 6.16%. Calcd for C93H146F3N7O11: C, 70.02; H, 9.23; N,
6.15%.
Bis{2-[3,4-bis(undecyloxy)phenyl]ethyl} DL-glutamate (DL-
6b). Obtained in a yield of 80% by the same procedure for
the preparation of 6b. Spectroscopic data of DL-6b were
identical to those of 6b.
Bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl} DL-glutamate (DL-
6d). Yield 54%. The chemical structure of DL-6d was assigned
by the comparison of the spectroscopic data of 6d.
Bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl} N-[N10-(trifluoroacetyl)-
pteroyl]-L-glutamate (1d). Yield 29%. Yellow waxy solid. Phase
transition temperature (DSC on heating): Dho 62 Dhd 207 NC 223
Iso. Rf~0.62 (CHCl3–MeOH~6 : 1). IR 2919, 2851, 1718, 1701,
1541, 1508, 1265, 1212, 1161, 852, 802 cm21; 1H NMR (400 MHz)
d~8.81 (s, 1 H), 7.88 (d, J~8 Hz, 2 H), 7.43 (d, J~8 Hz, 2 H),
6.60–6.79 (m, 6 H), 5.17 (s, 2 H), 4.69–4.78 (m, 1 H), 4.13–4.23 (m, 4
H), 3.38–4.08 (m, 8 H), 2.75–2.95 (m, 4 H), 2.30–2.52 (m, 2 H), 2.17–
2.33 (m, 1 H), 1.99–2.11 (m, 1 H), 1.67–1.82 (m, 8 H), 0.95–1.52 (m,
120 H), 0.86 (t, J~7 Hz, 12 H); 19F NMR (282 MHz) d~267.4;
MALDI-TOF MS (IAA) m/z 1820.9 (Mz2, C109H178F3N7O11
requires 1820.4). Found: C, 69.67; H, 9.67; N, 5.25%. Calcd for
Representative procedure for the preparation of 1: bis{2-[3,4-bis-
(undecyloxy)phenyl]ethyl} N-[N10-(trifluoroacetyl)pteroyl]-L-
glutamate (1b)
N10-(Trifluoroacetyl)pteroic acid{15a (0.67 g, 1.65 mmol) was
charged in an oven-dried, 100 mL, two-necked, round-
bottomed flask, equipped with a rubber septum and magnetic
stirring bar and dried over P2O5 for 24 h at 40 uC. Then
anhydrous DMF (5 mL) was added into the flask under an
argon atmosphere. The resulting suspension was stirred at
40 uC until all the solid dissolved. To the dark red solution was
slowly added dropwise triethylamine (0.27 mL, 1.98 mmol) and,
subsequently, isobutyl chloroformate (0.24 mL, 1.82 mmol) at
0 uC. The mixture was protected from light and stirred at room
temperature for 1 h before a solution of 6b (1.89 g, 1.82 mmol)
in THF (15 mL) was slowly added dropwise. The resulting
mixture was stirred at 40 uC for 3 days, the solvent was
removed in vacuo, and the residue was dissolved in CHCl3–
EtOH–benzene (15 : 1 : 1). The solution was then filtered
through a pad of Celite to remove a trace of solid residue.
The filtrate was concentrated in vacuo and purified by silica
gel flash column chromatography (eluent: CHCl3–EtOH–
benzene~13 : 1 : 1) to give 1b as a mesomorphic yellow waxy
C109H178F3N7O11?0.5CHCl3: C, 69.98; H, 9.57; N, 5.22%.
Bis{2-[3,4-bis(undecyloxy)phenyl]ethyl} N-[N10-(trifluoroacetyl)-
pteroyl]-DL-glutamate (DL-1b). Compound DL-1b was obtained
in a yield of 24% by the same procedure as for the preparation
of 1b as a yellow waxy solid. Phase transition temperatures
(DSC on heating): Cr 25 S 235 Iso. Spectroscopic data of
DL-1b were consistent with 1b.
Bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl} N-[N10-(trifluoroacetyl)-
pteroyl]-DL-glutamate (DL-1d). Preparation of DL-1d was carried
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out by the same procedure as for the synthesis of 1d. Yield 49%.
Yellow waxy solid. Phase transition temperatures (DSC on
heating): Dho 63 Dhd 207 NC 225 Iso. Assignment of the
structure of DL-1d was carried out by comparison of the
spectroscopic data with those of 1d.
After evaporation of the solvent in air, the thin layer of 1 on the
substrate was momentarily exposed to a flame to melt. The
resulting sample was annealed on a hot stage at 140 uC for 4 h,
and then cooled to room temperature overnight under a
nitrogen atmosphere.
Infrared measurements for hydrogen-bonded assemblies
Synthesis of bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl}
N-benzyloxycarbonyl-L-aspartate (9)
The samples for the measurements were prepared as follows:
the samples of 1 were sandwiched between two thin pellets of
KBr at 140 uC, and the sample was heated to 250 uC followed
by cooling to room temperature. The formation of smectic or
discotic phases was checked by using a polarizing microscope.
Characterization of the hydrogen-bonded patterns of 1 was
carried out using a JASCO FT/IR-8900m equipped with a
MICRO-20 microsampling FTIR spectrometer at room
temperature.
Compound 9 was prepared by a similar procedure to that for
the preparation of 5 as a colorless solid in a yield of 94%. Mp
88.5–88.8 uC. Rf~0.47 (hexane–EtOAc~5 : 1). IR 3321, 2956,
2918, 2850, 1726, 1685, 1541, 1521, 1469, 1294, 1264, 1234,
1159, 1141, 999, 721 cm21; 1H NMR (400 MHz) d~7.23–7.48
(m, 5 H), 6.62–6.80 (m, 6 H), 5.71 (d, J~8 Hz, 1 H), 5.12 (s, 2
H), 4.57–4.64 (m, 1 H), 4.30 (t, J~7. Hz, 2 H), 4.21 (t, J~7.
Hz, 2 H), 3.92–4.02 (m, 8 H), 2.95–3.07 (m, 1 H), 2.75–2.90 (m,
5 H), 1.71–1.87 (m, 8 H), 1.02–1.55 (m, 120 H), 0.88 (t,
J~7 Hz, 12 H); 13C NMR (100 MHz) d~170.6, 170.5, 155.9,
149.2, 148.0, 147.9, 136.1, 129.9, 129.8, 128.5, 128.2, 128.0,
121.03, 121.00, 114.7, 114.6, 114.1, 69.34, 69.27, 67.1, 66.4,
65.7, 50.4, 36.6, 34.5, 31.9, 29.5, 29.38, 29.36, 26.07, 26.06, 22.7,
14.1; MALDI-TOF MS (IAA) m/z 1572.5 (Mz1zNaz,
Complexation of alkali metal salts with folic acid derivatives
All alkali metal salts mixtures of 1 were prepared by slow
evaporation from a THF solution containing the requisite
amounts of lithium, sodium, or potassium triflate with folic
acid derivatives 1 followed by drying overnight in vacuo.
C100H173NO10 requires 1572.3). Found: C, 77.70; H, 11.47%.
Calcd for C100H173NO10: C, 77.52; H, 11.25%.
Acknowledgements
Preparation of bis{2-[3,4-bis(octadecyloxy)phenyl]ethyl}-L-
aspartate (10)
This work was financially supported by the Japan Society for
the Promotion of Science (Grant-in-Aid for Scientific Research
(C) No. 12650864) and by the SHISEIDO Grant for Science
and Technology Research 2000. We thank Professor J. W.
Goodby, Dr V. Vill, and Professor A. Matsuda for helpful
discussions.
Preparation of 10 was carried out by the procedure for the
preparation of 6. Yield 38%. Pale yellow solid, mp~68.2–
68.7 uC. Rf~0.66 (CH2Cl2–MeOH~10 : 1). IR 3446, 2918,
2850, 1733, 1520, 1471, 1267, 1235, 1140, 1070, 1022, 805,
1
721 cm21; H NMR (400 MHz) d~6.71–6.90 (m, 6 H), 4.18–
4.21 (m, 4 H), 3.93–4.07 (m, 8 H), 3.77 (dd, J~7, 5 Hz, 1 H),
2.81–2.93 (m, 4 H), 2.77 (dd, J~16, 5 Hz, 1 H), 2.67 (dd, J~16,
7 Hz, 1 H), 1.79–1.93 (m, 8 H), 1.12–1.60 (m, 120 H), 0.88 (t,
J~7 Hz, 12 H); 13C NMR (100 MHz) d~174.0, 171.1, 149.10,
149.09, 147.87, 147.86, 130.0, 129.9, 121.0, 114.6, 114.5, 113.9,
69.3, 69.2, 65.9, 65.5, 51.1, 38.9, 38.8, 4.5, 31.9, 29.7, 29.6,
29.45, 29.36, 29.32, 26.0, 22.7, 14.1. MALDI-TOF MS (IAA)
m/z 1438.3 (Mz1zNaz, C92H167NO8 requires 1438.3).
Found: C, 77.82; H, 11.77%. Calcd for C92H167NO8: C,
78.07; H, 11.89%.
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1516, 1508, 1469, 1264, 1212, 1161, 1072, 721 cm21; H NMR
(400 MHz) d~8.34 (s, 1 H), 7.76–7.90 (m, 2 H), 7.36–7.49 (m, 2
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69.93; H, 9.69; N, 5.14%. Calcd for C108H176F3N7O11?
0.5CHCl3: C, 69.86; H, 9.54; N, 5.26%.
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6
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AFM measurements of folic acid derivatives on a Si surface
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9
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