Self-assembly of vesicles from the stacking of a dipodal F?H-N hydrogen bonded arylamide foldamer

Article abstract of DOI:10.1016/j.tet.2009.10.073

In this paper, we report the synthesis and self-assembling behavior of an F?H-N hydrogen bonding-induced arylamide-based dipodal foldamer. SEM, AFM, TEM, and XRD studies reveal that this preorganized oligomer stacks to form vesicles in methanol-chloroform

Full text of DOI:10.1016/j.tet.2009.10.073

Tetrahedron 65 (2009) 10544–10551
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Tetrahedron
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Self-assembly of vesicles from the stacking of a dipodal F/H–N hydrogen
bonded arylamide foldamer
,
Lu Wang a, Ze-Yun Xiao a, Jun-Li Hou b, Gui-Tao Wang a, Xi-Kui Jiang a, Zhan-Ting Li a
*
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
b Department of Chemistry, Fudan University, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, we report the synthesis and self-assembling behavior of an F/H–N hydrogen bonding-
induced arylamide-based dipodal foldamer. SEM, AFM, TEM, and XRD studies reveal that this preor-
ganized oligomer stacks to form vesicles in methanol–chloroform (10–70%) binary solvents due to the
strong stacking interaction of the folded segments and the supramolecular polymeric feature of the
dipodal molecule in the stacked state. In contrast, a simple folded molecule can give rise to vesicles only
when the chloroform content is 45–55%.
Received 13 September 2009
Received in revised form 20 October 2009
Accepted 22 October 2009
Available online 28 October 2009
Keywords:
Foldamer
Ó 2009 Elsevier Ltd. All rights reserved.
Vesicles
Hydrogen bonding
Self-assembly
Stacking
Aromatic amides
1. Introduction
series of folded and related macrocyclic frameworks can stack with
fullerenes and coronene more strongly than the (Me)O/H–N hy-
Vesicles are unique spherical assemblies with applications in
biomimetics, nanomaterials, drug, and gene delivery.1,2 Inspired by
the formation of liposomes from the natural amphiphilic
phospholipid in aqueous media driven by the hydrophobic force,
chemists have designed an ocean of amphiphilic aliphatic
molecules and macromolecules for the assembly of vesicles.3–6
Another principle for the generation of vesicles concerns the
drogen bonded arylamide counterparts,12 because the ether methyl
groups in the latter system have an important steric hindrance for
any intermolecular stacking. Considering that several (Me)O/H–N
hydrogen bonding-induced arylamide foldamers have been
revealed to assemble into vesicles or organogels in polar organic
solvents,13 we became interested in designing new F/H–N hy-
drogen bonding-induced foldamers to produce vesicular structures,
because the self-stacking of this series of frameworks might be
stronger than their (Me)O/H–N hydrogen bonding-induced
analogs. To further enhance the stacking interaction, we have
prepared a dipodal foldamer monomer. We envisioned that it
might form supramolecular polymeric structures in the stacked
state in polar media,14 which would facilitate the formation of
extended membranes and thus vesicles. In this paper, we report the
detailed results.
utilization of the solvophobically driven
p stacking of rationally
designed aromatic monomers. In this context, quite a number of
rigid and straight oligo(p-phenylene)- and oligo(p-phenylene
vinylene)-based building blocks have been developed.7,8 Examples
of ortho-phenylene ethynylene macrocyclic and linear arylamide
monomers have also been reported.9,10 We herein report a novel
approach for the self-assembly of vesicles in methanol–chloroform
binary solvents from a dipodal F/H–N hydrogen bonding-driven
arylamide foldamer by making the stacking interaction as the
driving force.
2. Results and discussion
We previously reported a class of arylamide foldamers, whose
rigid crescent conformations are stabilized by the intramolecular
F/H–N hydrogen bonding.11 More recently, we found that this
Dipodal compound T1 and simple foldamer T2 were prepared.
The N,N-dioctylamide units were introduced to provide solubility
in organic solvents. A comparison of their self-assembling behav-
iors would reveal the possible cooperative effect of the two
connected foldamer segments of T1. The synthetic route for T1 is
* Corresponding author. Tel.: þ86 21 54925122; fax: þ86 21 64166128.
E-mail address: ztli@mail.sioc.ac.cn (Z.-T. Li).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.073

L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
10545
CO2Me
OMe
I
CO2 Me
OMe
provided in Scheme 1. Thus, ester 1 was first treated with I2 and
I2, Ag2SO4
Ag2SO4 in methanol to give 2 quantitatively. The latter was then
self-coupled in the presence of copper powder to give diphenyl 3 in
65% yield. Hydrolysis of 3 with potassium hydroxide in aqueous
methanol generated diacid 4, which was further treated with oxalyl
chloride to produce diacyl chloride 5. With this intermediate
available, compound 7 was prepared in 36% yield from 6 and
dioctylamine through the acyl chloride as intermediate and then
hydrogenated in the presence of Pd–C to give diamine 8 in 92%
yield. The latter was coupled with 2-fluorobenzoic acid to give 9 in
60% yield. This aniline was further coupled with 10 to afford ester
11 in 75% yield, which was then hydrolyzed with potassium
hydroxide to give acid 12 in 95% yield. The acid was treated with
oxalyl chloride to produce the corresponding acyl chloride, which
was then coupled with 8 to give amine 13 in 52% yield. Finally,
compound 13 was reacted with 5 in THF to afford T1 in 81% yield,
while its reaction with 14 under the similar conditions gave T2 in
71% yield.
MeOH, r.t., 0.5 h
99%
1
2
OMe
CO2 Me
Cu-powder
KOH, MeOH
reflux, 12 h, 96%
210-220 °C, 4 h, 65%
CO2 Me
3
OMe
OMe
OMe
CO2H
COCl
(COCl)2, DMF(cat.)
THF, r.t., 0.5 h
CO2H
4
COCl
5
OMe
OMe
F
F
1) (COCl)2, DMF (cat.)
THF, r.t. 0.5h
O2N
NO2
O2N
NO2
O
O
2) HN(n-C8H17)2, THF
NEt3, r.t., 1 h, 36%
R
O
N
F
F
N
F
R
O
H
H
R
7
6
CO2H
F
N
N
H
F
H
2-fluorobenzoic acid
EDCI, HOBt, CH2Cl2
H2N
NH2
H2, Pd-C (10%)
MeO
r.t., 48 h, 60%
THF, r.t., 48 h, 92%
R
8
T1
OMe
H
F
H
F
O
R
N
N
O
R
F
MeO2C
CO2H
10
F
F
F
O
R
NH
F
H
H
O
R
NH
N
O
F
N
F
EDCI, HOBt, CH2Cl2
r.t., 48 h, 75%
O
NH
F
O
O
H
NH2
CO2Me
11
O
R
N
F
N
R
O
9
H
H
F
F
F
O
N
N
H
F
i) (COCl)2, DMF(cat.)
THF, r.t., 0.5 h
R = CO(n-C8H17
)
O
R
NH
MeO
2
KOH, THF
F
T2
r.t., 4.5 h
95%
ii) 8, NEt3, THF
r.t., 1 h, 52%
NH
F
CO2H
12
O
Compounds T1 and T2 did not dissolve in methanol, but were
soluble in the chloroform–methanol mixture. Their capacity of
forming vesicles in this binary solvent system was first investigated
by SEM. The representative results are provided in Figure 1. It is
found that when the content of chloroform was 10–70%, T1 formed
vesicles in the binary solvents (Fig. 1a–d). Several vesicles showed
defects (holes), suggesting that the vesicles were hollow. The
images also revealed that, with the increase of the content of
chloroform (from 60%), the vesicles began to fuse and when the
content was 80%, no vesicular structures could be observed and the
images showed only membrane-like structures (Fig.1e). Compound
T2 also gave rise to vesicles in the binary media, but only when the
content of chloroform was in the narrow range of 45–55% (Fig. 1g
and h). Below this range, it formed foam-like structures (Fig. 1f) and
above the range, like T1, it generated membrane-like structures.
Both compounds should stack in the binary solvents. However, the
greater capacity of T1 of forming vesicles in the more and less polar
solvent systems should reflect its stronger stacking due to its larger
aromatic framework. The biphenyl moiety usually has a relatively
large torsion angle. Therefore, this greater stacking should be
driven by the cooperative interaction of the two arylamide
segments due to the F/H–N hydrogen bonding-induced folded
conformation. Such intramolecular three-center hydrogen bonding
O
O
R
NH
F
HN
R
5, THF, NEt3
r.t., 3 h, 81%
F
F
T1
O
NH
NH2
13
F
R = CO(n-C8H17
)
2
COCl
OMe
13, THF, NEt3
T2
r.t., 3 h, 85%
14
Scheme 1. The synthetic routes for compounds T1 and T2.
has been revealed to survive in polar media.13,15 Moreover, in the
stacked state, the hydrogen bonding sites should be, to some
extent, shielded from the methanol molecules and therefore
induced a more rigid folded state.
AFM images also supported T1 and T2 formed the vesicles. The
result of T1 is shown in Figure 2. Different from the SEM results, the
sizes of the vesicles were generally smaller than the related ones,

10546
L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
Figure 1. SEM images obtained by evaporation of the solutions (0.4 mM) in the CHCl3/MeOH mixtures of varying ratios on the mica plates. T1: a) 10%, b) 30%, c) 50%, d) 70%, and e)
80%; T2: f) 10%, g) 30%, h) 50%. The values are the content (v%) of CHCl3 in the binary solvents.
because the image was obtained from a solution of lower concen-
tration for achieving a high resolution. Cross-section analysis of the
typical structures revealed that the diameter-height ratios were ca.
16.1 for T1 and 9.2 for T2, which indicated that they were of
flattened shape. The results also supported that the spherical
structures were hollow and contained solvent molecules,16 which
were evaporated after being transferred from solution to the mica
surface.
TEM images further supported the formation of the vesicles by
T1 and T2 (Fig. 3). The clear contrast between the peripheral and
central areas of the spherical aggregates supported their hollow
nature, which is typically produced by the projection of the hollow

L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
10547
which rendered it soluble in the chloroform–methanol mixture.
Fluorescence studies showed that the similar interaction also oc-
curred between it and T1, because adding G1 to the solution of T1
in chloroform–methanol (1:1) caused a substantial reduction of
the emission intensity of T1. Job’s plot revealed a 1:1 stoichiom-
etry for G1 and the folded segment of T1. On the basis of a non-
linear regression, the apparent association constant for the com-
plex of the folded segment of T1 and G1 was estimated to be ca.
2.2ꢀ104 Mꢁ1. SEM images revealed that, adding 1 equiv of G1 to
the solution of T1 in chloroform–methanol (1:1) completely
inhibited the formation of the vesicles by T1 and the mixture gave
rise to fibrous structures. This observation indicated that, the
vesicles of T1 were formed through its ordered stacking, which
was weakened in the presence of G1 due to its strong stacking
with T1. This latter stacking was less directional due to the global
feature of G1 and therefore only lead to the formation of fibrous
structures of less order.
The vesicular aggregates in chloroform and methanol (1:1) were
further investigated by the dynamic light scattering (DLS)
measurements. The results showed that the vesicles formed by
both compounds had a relatively narrow size distribution (Fig. 6),
with the intensity-average diameters being 1280 and 615 nm,
respectively. The vesicle dimension obtained from the DLS analysis
is reasonably in agreement with the SEM studies. The diameter
calculated from the DLS analysis is smaller than that observed in
the SEM studies (ca. 800 nm), which can be attributed to the
vesicles’ flattening in the SEM measurements after being trans-
ferred from solution to surface.
1H NMR dilution experiments showed no important shifting
(<0.02 ppm) for the signals in the downfield area, indicating that
the folded arylamide structures did not aggregate in pure chloro-
form. However, reducing the concentration of T1 in the mixture of
chloroform-d and methanol-d4 (1:1, v/v) from 3.0 mM to 0.3 mM
caused the signals of several aromatic protons to shift downfield
notably (up to 0.21 ppm). Similar shifting, albeit smaller, was also
observed for T2. These results further supported that both
compounds aggregated through the stacking interaction in the
polar media.
Figure 2. Tapping-mode AFM images (spin-coating) and cross-section analysis of T1,
obtained on mica surface by evaporation of the solution (0.01 mM) in CHCl3 and MeOH
(1:1).
spheres.17 High resolution TEM images highlighted that the wall
thickness of the vesicular assemblies of both compounds were
about 2.8 nm, which was close to the sum of the calculated width
(2.6 nm) of their crescent backbones and the length of the extended
side chains. Considering that the stacked molecules should exhibit
a larger apparent size than that of a single molecule, this result
suggested that the vesicles had a monolayer morphology.
The X-ray diffraction (XRD) measurement of the solid sample of
T1, obtained by evaporating its solution in chloroform–methanol
(1:1) revealed a peak at 0.42 nm, which supported a less compact
stacking mode (Fig. 4), as observed in other stacked supramolecular
aggregates.18 A similar peak was also observed for T2, which was,
however, broader and weaker in strength. These results are
consistent with the SEM observations, reflecting that the stacking
interaction existed for both compounds, but it is stronger for T1 as
a result of the large framework of the dipodal molecule. Both
compounds also exhibited a strong peak at 1.51 nm, which is
consistent with their calculated size of the folded frameworks
(1.52 nm) and thus further supported the monolayer stacking of the
molecular in forming the vesicles. The result also indicated that
dipodal T1 mainly stacked along its long ‘S’-styled framework
rather than the line across the biphenyl moiety (Fig. 5). Molecular
dynamic calculation showed that the conformation was more sta-
ble than the ‘C’-styled conformation. By adopting this stacking
pattern, it could form supramolecular polymers to facilitate the
formation of the vesicles. The stacking of T2 was relatively simple
and should be similar to that reported for (Me)O/H–N hydrogen
bonding-induced arylamide foldamers,13 although the orientation
of the molecules in the column-styled aggregates might be differ-
ent (Fig. 5).
3. Conclusions
In this study, we describe a systematic study of the self-as-
sembly of one F/H–N hydrogen bonding-driven dipodal foldamer
into vesicular structures. Previous investigations show that the
formation of vesicles from (Me)O/H–N hydrogen bonded
foldamers is co-driven by the stacking and intermolecular hydro-
gen bonding in more polar methanol, the present formation of
vesicles do not need the involvement of the intermolecular
hydrogen bonding due to the enhanced stacking of the folded
segments. Because the F/H–N hydrogen bonded foldamers are
robust in binding alkyl ammoniums, as the next step, we foresee
performing the cross-membrane transportation of the organic
cations utilizing the new vesicles. It will be also of interest to
prepare tri- or tetrapodal foldamers, which might exhibit new
unique supramolecular polymeric features due to the robust
stacking of the preorganized segments.
4. Experimental section
4.1. General methods
All reactions were carried out under a dry nitrogen atmosphere.
All solvents were dried before use following the standard
procedures. Unless otherwise indicated, all starting materials were
obtained from commercial suppliers and were used without further
purification. Analytical thin-layer chromatography (TLC) was
It has been revealed that the F/H–N hydrogen bonding-in-
duced arylamide foldamers stack strongly with C60.
12a To get more
insight into the assembling mechanism of dipodal T1, compound
G1 was also prepared (Scheme 2), the long aliphatic chains of

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L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
Figure 3. TEM images of T1 at different scales (a–c) and T2 (d), obtained from the solutions (0.25 mM) in CHCl3 and MeOH (1:1).
performed on 0.2 mm silica 60 coated on glass plates with F254
indicator. The 1H and 13C NMR spectra were recorded on 300 or
400 MHz spectrometers in the indicated solvents. Chemical shifts
removal of the solvent under reduced pressure, compound 2 was
obtained as a white solid (4.07 g, 99%). 1H NMR (300 MHz, CDCl3):
d
8.07 (d, J¼2.3 Hz, 1H), 7.73 (dd, J1¼8.8 Hz, J2¼2.4 Hz, 1H), 6.76 (d,
are expressed in parts per million (
as internal standards (1H: chloroform:
2.49 ppm; 13C: CDCl3: 77.2 ppm). Elemental analysis was carried
d) using residual solvent protons
J¼8.8 Hz, 1H), 3.88 (s, 6H). MS (EI): m/z 292 [M]þ.
d
7.26 ppm; DMSO:
d
4.3. Compound 3
out at the SIOC analytical center. MALDI MS were obtained on
a Voyager-DE STR or IonSpec4.7 Tesla FTMS spectrometer (CHCA or
DHB as matrix). SEM images were obtained with a JEOL model
JSM-6390LV and the dry samples obtained were shielded with Pt.
AFM pictures were obtained in ‘tapping’ mode on a multimode SPM
system equipped with a Nanoscope IV controller. LR-TEM images
were recorded on a JEOL JEM-1230 microscope. HR-TEM images
were recorded on a JEOL JEM-2010 microscope equipped with
energy-dispersive X-ray spectroscopy. The DLS measurement was
performed on a Malvern Zetasizer Nano ZS apparatus. XRD exper-
iment was carried out on a Bruker Avance D8 X-ray diffractometer.
An intimate mixture of compound 2 (1.35 g, 4.62 mmol) and
activated copper bronze (3.50 g, 54.6 mmol) was heated under
argon at 210–220 ꢂC for 4.5 h and then cooled. The mixture was
exhaustively extracted with boiling ethyl acetate (30 mLꢀ2) and
the extracts were concentrated with a rotavapor. After workup, the
resulting residue was purified by column chromatography (AcOEt/
petroleum ether 1:3) to give compound 3 as a white solid (0.47 g,
63%). 1H NMR (300 MHz, CDCl3):
J1¼8.6 Hz, J2¼2.4 Hz, 2H), 6.76 (d, J¼8.7 Hz, 2H), 3.94 (s, 6H), 3.92 (s,
d
8.00 (d, J¼2.4 Hz, 2H), 7.73 (dd,
6H). 13C NMR (125 MHz, CDCl3):
d 166.5, 158.3, 131.8, 131.4, 126.7,
120.2, 112.4, 56.1, 52.1. MS (EI): m/z 330 [M]þ. Anal. Calcd for
C18H18O6: C, 65.45; H, 5.49. Found: C, 65.33; H, 5.59.
4.2. Compound 2
A suspension of compound 1 (2.34 g, 14.1 mmol), iodine (4.06 g,
16.0 mmol) and silver sulfate (5.61 g, 18.0 mmol) in methanol was
stirred at rt for 0.5 h and then the solid filtrated off. The filtrate was
treated with saturated aqueous sodium sulfite solution until the
violet color disappeared and then concentrated under reduced
pressure. The resulting residue was extracted with dichloro-
methane (20 mL) and the organic phase washed with water
(20 mLꢀ2) and brine (20 mL), and dried over sodium sulfate. Upon
4.4. Compound 4
A solution of compound 3 (0.10 g, 0.30 mmol) and potassium
hydroxide (0.34 g, 6.07 mmol) in water (7.5 mL) and THF (15 mL)
was stirred under reflux for 6 h and then concentrated under
reduced pressure. The resulting residue was acidified with hydro-
chloric acid to pH¼1, and then the mixture extracted with ethyl
acetate (50 mLꢀ3). The combined organic phase was washed with

L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
10549
O
O
(a)
C60, I2, DBU
1.51 nm
n-C16H33
O
OC16H33-n
toluene, r.t, 4 h, 37%
3000
2000
1000
0
15
0.42 nm
O
n-C16H33
Scheme 2. The synthesis of compound G1.
O
O
OC16H33-n
G1
0
10
20
2-Theta Angle
30
40
4.5. Compound 7
(b)
4000
3000
2000
1000
0
To a solution of compound 619 (4.00 g, 17.5 mmol) and DMF
(0.02 mL) in THF (50 mL), cooled in an ice-bath, was added oxalyl
chloride (4.00 mL, 42.1 mmol) dropwise. The mixture was stirred at
rt for 0.5 h and then concentrated with a rotavapor. The resulting
oily residue was dissolved in THF (20 mL) and the solution was
cooled to ꢁ10 ꢂC. Then, under stirring, to this solution was added
a solution of di-n-octyl amine (6.00 mL, 19.8 mmol) and triethyl-
amine (6.00 mL, 43.2 mmol) in THF (20 mL) dropwise. After stirring
for another 1 h, the solvent was removed under reduced pressure.
The resulting residue was triturated in chloroform (50 mL). The
organic solution was washed with water (30 mLꢀ2) and brine
(20 mL), and then dried over sodium sulfate. The solvent was
removed with a rotavapor, the resulting residue was purified by
column chromatography (AcOEt/petroleum ether 1:20) to give
compound 7 as a yellow oil (4.20 g, 53%). 1H NMR (300 MHz,
1.51 nm
0.42 nm
0
10
20
2-Theta Angle
30
40
Figure 4. XRD profiles of the aggregates of a) T1 and b) T2. The samples were prepared
by evaporating their solutions (0.4 mM) in CHCl3 and MeOH (1:1).
CDCl3):
d
8.33 (d, J¼6.0 Hz, 2H), 3.48 (t, J¼5.4 Hz, 2H), 3.20
water (50 mLꢀ2) and brine (50 mL), and dried over sodium sulfate.
Removal of the solvent under reduced pressure afforded compound
4 as a white solid (0.09 g, 96%). 1H NMR (300 MHz, DMSO-d6):
(t, J¼5.4 Hz, 2H), 1.29–1.26 (m, 24H), 0.89 (t, J¼2.1 Hz, 6H). 19F NMR:
d
ꢁ123.7 (t, J¼6.0 Hz,1F). This compound was unstable and used for
the next step immediately after chromatography.
d
12.84 (s, 2H), 7.92–7.85 (m, 4H), 7.27 (s, 2H), 3.95 (s, 6H). MS (EI):
m/z 302 [M]þ.
(a)
40
1280 nm
30
20
10
0
10
100
1000
Size (nm)
10000
(b)
40
30
20
10
0
615 nm
100
1000
Size (nm)
10000
Figure 5. Proposed stacking model of a) T1 and b) T2 for the formation of the vesicle
walls.
Figure 6. The DLS intensity-weighted distribution of the vesicular aggregates of a) T1
and b) T2 in the solution (0.4 mM) of chloroform and methanol (1:1).

10550
L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
4.6. Compound 8
4.9. Compound 12
A suspension of compound 7 (1.00 g, 2.20 mmol) and Pd–C
(0.1 g) in THF (20 mL) was stirred under hydrogen gas atmosphere
(15 psi) at rt for 48 h. The solid was filtered off and the filtrate
concentrated under reduced pressure to give compound 8 as a pale
A solution of compound 11 (0.25 g, 0.36 mmol) and potassium
hydroxide (0.19 g, 3.39 mmol) in water (9 mL) and THF (18 mL) was
stirred at rt for 4.5 h and then concentrated under reduced pres-
sure. The resulting residue was acidified with hydrochloric acid to
pH¼1, and then the mixture was extracted with ethyl acetate
(15 mLꢀ3), the combined organic phase was washed with water
(20 mLꢀ2) and brine (20 mL), and dried over sodium sulfate. Upon
removal of the solvent under reduced pressure, compound 12 was
obtained as a white solid (0.24 g, 95%). 1H NMR (300 MHz, CDCl3):
yellow solid (0.80 g, 92%). 1H NMR (300 MHz, CDCl3):
d 6.17
(d, J¼7.8 Hz, 2H), 3.72 (s, 4H), 3.43 (t, J¼5.4 Hz, 2H), 3.20
(t, J¼5.4 Hz, 2H),1.32–1.29 (m, 24H), 0.89 (t, J¼5.4 Hz, 6H). 19F NMR:
d
ꢁ157.5 (t, J¼9.0 Hz, 1F). LR-MS (MALDI-TOF): m/z 394.3 [MþH]þ.
Anal. Calcd for C23H36FN3O: C, 70.19; H, 10.24; N, 10.68. Found: C,
70.53; H, 10.03; N, 10.32.
d
8.85–8.71 (m, 2H), 8.40–8.31 (m, 2H), 8.26 (d, J¼8.5 Hz, 1H), 8.21–
8.12 (m, 2H), 7.60–7.53 (m, 1H), 7.53–7.19 (m, 3H), 3.45 (t, J¼7.2 Hz,
2H), 3.25 (t, J¼7.2 Hz, 2H), 1.62–1.55 (m, 6H), 1.33–1.08 (m, 18H),
4.7. Compound 9
0.89–0.77 (m, 6H). 19F NMR:
d
ꢁ112.2 (s, 1F), ꢁ113.1 (s, 1F), ꢁ142.7
(s, 1F). 13C NMR (125 MHz, CDCl3):
d 171.0, 165.8, 162.0, 161.5, 161.3,
To a stirred solution of compound 8 (0.28 g, 0.71 mmol) and
2-fluorobenzoic acid (0.10 g, 0.71 mmol) in dichloromethane
(2.0 mL) were added EDCI (0.15 g, 0.78 mmol) and HOBt (0.11 g,
0.81 mmol). The solution was stirred at rt for 48 h and then di-
luted with dichloromethane (30 mL). The solution was washed
with water (20 mLꢀ2) and brine (20 mL), and dried over sodium
sulfate. Upon removal of the solvent under reduced pressure, the
resulting residue was purified by column chromatography
(AcOEt/CH2Cl2 1:10) to give compound 9 as a white solid (0.21 g,
161.0, 159.5, 158.7, 145.4, 143.0, 136.9, 134.6, 134.5, 133.1, 132.5,
126.6, 126.5, 126.2, 126.1, 125.4, 124.8, 122.2, 122.1, 120.8, 120.6,
120.2, 117.3, 116.6, 116.5, 116.4, 49.9, 45.9, 32.1, 32.0, 29.6, 29.5, 29.3,
28.9, 27.7, 27.4, 26.9, 22.9, 22.8, 14.3, 14.2. MS (ESI): m/z 718.6
[MþNa]þ, 734.5 [MþK]þ. HRMS (ESI): Calcd for C38H47N3O5F3
[MþH]þ: 682.3468. Found: 682.3462.
4.10. Compound 13
57%). 1H NMR (300 MHz, CDCl3):
d
8.78 (d, J¼8.8 Hz, 1H), 8.18 (t,
To a solution of compound 12 (0.25 g, 0.37 mmol) and DMF
(0.02 mL) in THF (15 mL), cooled in an ice-bath, was added oxalyl
chloride (0.60 mL, 6.31 mmol) dropwise. The mixture was stirred at
rt for 0.5 h and then concentrated under reduced pressure. The
resulting residue was dissolved in THF (10 mL) and the solution
cooled to ꢁ10 ꢂC. Then, to this stirred solution was added a solution
of compound 8 (0.22 g, 0.56 mmol) and triethylamine (0.5 mL,
3.60 mmol) in THF (10 mL) dropwise. After stirring for another 1 h,
the solution was concentrated under reduced pressure. The
resulting residue was triturated in chloroform (20 mL). The organic
solution was washed with water (10 mLꢀ2) and brine (10 mL), and
then dried sodium sulfate. Upon removal of the solvent in vacuo,
the crude product was purified by column chromatography (AcOEt/
CH2Cl2 1:2) to give compound 13 as a white solid (0.20 g, 52%). 1H
J¼8.2 Hz, 1H), 7.90 (t, J¼6.4 Hz, 1H), 7.58–7.51 (m, 1H), 7.35–7.17
(m, 2H), 6.61 (d, J¼8.1 Hz, 1H), 3.84 (s, 2H), 3.43 (t, J¼7.7 Hz, 2H),
3.25 (t, J¼7.7 Hz, 2H), 1.60–1.54 (m, 4H), 1.33–1.08 (m, 20H), 0.88–
0.80 (m, 6H). 19F NMR:
NMR (125 MHz, CDCl3):
d
ꢁ113.2–113.4 (m, 1F), ꢁ152.2 (s, 1F). 13
C
d 170.6, 161.6, 160.9, 159.2, 143.2, 140.8,
134.6, 134.5, 134.0, 133.9, 133.6, 133.5, 132.2, 126.2, 125.0 (d),
120.9, 120.8, 116.3, 116.0, 111.1 (d), 109.4, 49.2, 44.9, 31.7, 29.6,
29.3, 29.2, 29.0, 28.6, 27.5, 27.1, 26.6, 22.6, 14.0. MS (EI): m/z 515
[M]þ. HRMS (EI): Calcd for C30H44N3O2F2 [MþH]þ: 516.3403.
Found: 516.3396.
4.8. Compound 11
To a solution of compound 1020 (0.10 g, 0.51 mmol) and DMF
(0.02 mL) in THF (10 mL), cooled in an ice-bath, was added oxalyl
chloride (1.00 mL, 10.5 mmol) dropwise. The mixture was stirred
at rt for 0.5 h and then concentrated under reduced pressure. The
resulting oily residue was dissolved in THF (10 mL) and the solu-
tion cooled to ꢁ10 ꢂC. Then, under stirring, to this solution was
added a solution of compound 9 (0.25 g, 0.48 mmol) and trie-
thylamine (0.5 mL, 3.60 mmol) in THF (10 mL) dropwise. Stirring
was continued for another 1 h and the solvent was then removed
under reduced pressure. The resulting residue was triturated in
chloroform (20 mL). The organic solution was washed with water
(10 mLꢀ2) and brine (10 mL), and then dried over sodium sulfate.
Upon removal of the solvent in vacuo, the crude product was
purified by column chromatography (AcOEt/CH2Cl2 1:15) to give
compound 11 as a white solid (0.25 g, 75%). 1H NMR (300 MHz,
NMR (300 MHz, CDCl3):
d
9.05 (d, J¼10.88 Hz, 1H), 8.90 (d,
J¼10.8 Hz, 1H), 8.77 (d, J¼12.0 Hz, 1H), 8.30 (d, J¼5.5 Hz, 1H), 8.22–
8.16 (m, 2H), 8.12–8.06 (m, 2H), 7.80 (d, J¼5.5 Hz, 1H) 7.56–7.50 (m,
1H), 7.43 (t, J¼7.8 Hz, 1H), 7.31–7.14 (m, 2H), 6.58 (d, J¼8.0 Hz, 1H),
3.92 (s, 2H), 3.40–3.37 (m, 4H), 3.24–3.21 (m, 4H), 1.68–1.58 (m,
12H), 1.44–0.96 (m, 36H), 0.89–0.76 (m, 12H). 19F NMR:
d
ꢁ112.9 (s,
1F), ꢁ115.5 (s, 1F), ꢁ143.6 (s, 1F), ꢁ150.9 (s, 1F). 13C NMR (125 MHz,
CDCl3):
d 170.8, 170.1, 161.6, 161.5, 161.3, 160.9, 159.1, 159.0, 156.5,
145.2, 143.4, 142.8, 141.1, 134.9, 134.8, 134.1, 134.0, 133.1, 131.9, 126.3,
126.2, 126.0, 125.9, 125.8, 125.7, 124.9, 123.2, 123.0, 122.9, 122.7,
120.6, 120.5, 117.1, 116.3, 116.0, 115.9, 111.1, 109.5, 49.4, 49.2, 45.2,
44.9, 31.8, 31.7, 29.6, 29.3, 29.2, 29.0, 28.9, 28.5, 27.2, 27.1, 26.5, 22.6,
22.5, 14.0, 13.9. MS (MALDI-TOF): m/z 1079.6 [MþNa]þ. HRMS
(MALDI-TOF): Calcd for C61H85N6O5F4 [MþH]þ: 1057.6505. Found:
1057.6512.
CDCl3):
d
8.87–8.78 (m, 2H), 8.38–8.31 (m, 2H), 8.26 (d, J¼9.0 Hz,
1H), 8.21–8.12 (m, 2H), 7.60–7.53 (m, 1H), 7.53–7.19 (m, 3H), 3.94
4.11. Compound T1
(s, 3H), 3.45 (t, J¼7.2 Hz, 2H), 3.25 (t, J¼7.2 Hz, 2H), 1.62–1.55 (m,
6H), 1.33–1.08 (m, 18H), 0.89–0.77 (m, 6H). 19F NMR:
d
ꢁ112.6–
To a solution of compound 4 (0.01 g, 0.03 mmol) and DMF
(0.02 mL) in THF (4 mL), cooled in an ice-bath, was added oxalyl
chloride (0.20 mL, 2.10 mmol) dropwise. The mixture was stirred at
rt for 0.5 h and then concentrated under reduced pressure to give
compound 5 as a solid. The intermediate was dissolved in THF
(2 mL) and the solution was cooled to ꢁ10 ꢂC. Then, to this solution
under stirring, was added a solution of compound 13 (0.08 g,
0.08 mmol) and triethylamine (0.20 mL, 1.44 mmol) in THF (2 mL)
dropwise. Stirring was continued for another 3 h and the solvent
112.7 (m, 1F), ꢁ113.2–113.3 (m, 1F), ꢁ145.3 (s, 1F). 13C NMR
(125 MHz, CDCl3):
d 169.9, 163.9, 161.7, 161.1, 160.7, 160.6, 159.2,
158.1, 144.6, 142.2, 136.6, 136.1, 134.3, 134.2, 133.9, 132.2, 126.3,
126.2, 125.9, 125.1, 124.7, 120.6, 120.5, 116.4, 116.1, 52.7, 49.4, 45.2,
31.8, 31.7, 29.4, 29.2, 29.0, 28.6, 27.5, 27.1, 26.6, 22.6, 22.5, 14.1, 14.0.
MS (MALDI-TOF): m/z 718.6 [MþNa]þ, 734.5 [MþK]þ. HRMS
(MALDI-TOF): Calcd for C39H49N3O5F3 [MþH]þ: 696.3609. Found:
696.3618.

L. Wang et al. / Tetrahedron 65 (2009) 10544–10551
10551
was then removed under reduced pressure. The resulting residue
was triturated in chloroform (20 mL). The organic solution was
washed with water (10 mLꢀ2) and brine (10 mL), and then dried
over sodium sulfate. Upon removal of the solvent in vacuo, the
crude product was purified by column chromatography (CH2Cl2/
MeOH 100:1) to give compound T1 as a white solid (0.06 g, 81%). 1H
reduced pressure. The resulting residue was purified by column
chromatography (first with CS2 to remove unreacted C60 and then
with toluene as eluent) to afford compound G1 as a dark brown
solid (47 mg, 37%). 1H NMR (300 MHz, CDCl3):
d
4.49 (t, J¼6.3 Hz,
4H), 1.84 (t, J¼7.2 Hz, 4H), 1.18–1.48 (m, 52H), 0.88 (t, J¼6.0 Hz, 6H).
13C NMR (CDCl3):
163.7, 145.4, 145.3, 145.2, 144.9, 144.7, 144.6,
d
NMR (300 MHz, CDCl3):
d
10.60 (s, 2H), 10.07 (s, 2H), 9.27 (d,
143.9, 143.1, 143.0, 142.2, 142.0, 141.0, 139.0, 71.8, 67.5, 31.9, 31.4,
30.2, 29.7, 29.6, 29.4, 29.3, 28.6, 26.0, 22.7, 14.1. LR-MS (MALDI-
TOF): m/z 1271 [MþH]þ. HRMS (MALDI-FT): Calcd for C95H67O4:
1271.5082. Found: 1271.5034.
J¼10.9 Hz, 2H), 8.89 (d, J¼19.7 Hz, 2H), 8.44 (d, J¼6.4 Hz, 2H), 8.39
(d, J¼5.5 Hz, 2H), 8.28–8.23 (m, 6H), 8.14–8.09 (m, 2H), 7.99 (s, 2H),
7.85 (s, 2H), 7.54–7.47 (m, 6H), 7.32–7.31 (m, 2H), 7.13–7.08 (m, 4H),
4.26 (s, 6H), 3.43–3.29 (m, 16H), 1.66–1.64 (s, 16H), 1.34–1.22 (m,
80H), 0.93–0.31 (m, 24H). 19F NMR:
d
ꢁ112.6 (s, 2F), ꢁ116.3 (s, 2F),
Acknowledgements
ꢁ144.6 (s, 2F), ꢁ144.7 (s, 2F). 13C NMR (125 MHz, CDCl3):
d 170.7,
170.1, 162.6, 162.2, 161.6, 161.3, 161.0, 159.2, 157.0, 156.8, 144.7, 144.2,
142.3,141.8,134.7,134.3, 133.7,132.9,132.3,131.3,130.7,129.0,127.3,
126.3, 126.1, 125.2, 124.9, 124.5, 124.3, 122.5, 122.3, 120.7, 120.3,
116.5, 116.2, 115.9, 115.8, 113.6, 111.9, 56.8, 49.5, 45.3, 31.9, 31.7, 29.7,
29.4, 29.2, 29.1, 28.7, 28.5, 27.4, 27.1, 26.5, 22.7, 22.5, 14.1, 13.9. MS
(MALDI-TOF): m/z 2380.4 [MþH]þ. HRMS (MALDI-FT): Calcd for
C138H179N12O14F8: 2380.3531. Found: 2380.3516.
We thank the National Science Foundation of China (Nos.
20732007, 20621062, 20572126, 20672137), the National Basic
Research Program (2007CB808000), the Science and Technology
Commission of Shanghai Municipality (09XD1405300) and the
Chinese Academy of Sciences for financial support.
References and notes
4.12. Compound T2
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vergne, J.-P.; Maan, J. C. J. Am. Chem. Soc. 2005, 127, 1112–1113; (b) Ajayaghosh,
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To a solution of 2-methoxybenzoic acid (15 mg, 0.10 mmol) and
DMF (0.02 mL) in THF (10 mL), cooled in an ice-bath, was added
oxalyl chloride (0.20 mL, 2.10 mmol) dropwise. The mixture was
stirred at rt for 0.5 h and then concentrated under reduced pressure
to give compound 14 as a solid. This intermediate was dissolved in
THF (5 mL) again and the solution was cooled to ꢁ10 ꢂC. Then, to
this solution under stirring a solution of compound 13 (50 mg,
0.05 mmol) and triethylamine (0.1 mL, 0.72 mmol) in THF (5 mL)
was added dropwise. Stirring was continued for another 3 h and the
solvent then removed under reduced pressure. The resulting
residue was triturated in chloroform (40 mL). The organic solution
was washed with water (20 mLꢀ2) and brine (20 mL) and then
dried over sodium sulfate. Upon removal of the solvent in vacuo,
the crude product was purified by column chromatography (CHCl3/
EtOAc 4:1) to give compound T2 as a white solid (48 mg, 85%). 1H
NMR (400 MHz, CDCl3):
d
10.42 (d, J¼3.2 Hz,1H), 9.41–9.38 (m, 2H),
8.94 (dd, J1¼2.7 Hz, J2¼16.4 Hz, 1H), 8.42 (dd, J1¼1.8 Hz, J2¼6.7 Hz,
1H), 8.27 (dd, J1¼1.6 Hz, J2¼6.6 Hz, 1H), 8.15–8.08 (m, 4H), 8.04 (dt,
J1¼1.8 Hz, J2¼7.9 Hz, 1H), 7.86 (dd, J1¼1.7 Hz, J2¼6.7 Hz, 1H), 7.50–
7.44 (m, 1H), 7.40–7.36 (m, 2H), 7.25–7.21 (m, 1H), 7.10 (dd, J1¼8.3,
J2¼12.2 Hz, 1H), 7.01–6.97 (m, 1H), 6.86 (d, J¼8.3 Hz, 1H), 4.00 (s,
3H), 3.39–3.17 (m, 8H), 1.58–1.53 (m, 8H), 1.30–1.12 (m, 40H), 0.88
(t, J¼6.3 Hz, 6H), 0.79–0.73 (m, 6H). 19F NMR:
d
ꢁ112.6 (s, 1F),
ꢁ112.3 (s, 1F), ꢁ142.7 (s, 1F), ꢁ113.1 (s, 1F). 13C NMR (125 MHz,
CDCl3):
d 170.3, 170.1, 162.9, 161.6, 161.5, 161.4, 161.2, 161.1, 159.1,
12. (a) Li, C.; Zhu, Y.-Y.; Yi, H.-P.; Li, C.-Z.; Jiang, X.-K.; Li, Z.-T.; Yu, Y.-H. Chem.d Eur. J.
2007, 13, 9990–9998; (b) Zhu, Y.-Y.; Li, C.; Li, G.-Y.; Jiang, X.-K.; Li, Z.-T. J. Org.
Chem. 2008, 73, 1745–1751.
13. Cai, W.; Wang, G.-T.; Xu, Y.-X.; Jiang, X.-K.; Li, Z.-T. J. Am. Chem. Soc. 2008, 130,
6936–6937; Cai, W.; Wang, G.-T.; Du, P.; Wang, R.-X.; Jiang, X.-K.; Li, Z.-T. J. Am.
Chem. Soc. 2008, 130, 13450–13459.
14. Supramolecular Polymers, 2nd ed.; Ciferri, A., Ed.; CRC: Boca Raton, 2005; p 761.
15. (a) Parra, R. D.; Zeng, H.; Zhu, J.; Zheng, C.; Zeng, X. C.; Gong, B. Chem.d Eur. J.
2001, 7, 4352–4357; (b) Yi, H.-P.; Wu, J.; Ding, K.-L.; Jiang, X.-K.; Li, Z.-T. J. Org.
Chem. 2007, 72, 870–877.
16. Yang, M.; Wang, W.; Yuan, F.; Zhang, X.; Li, J.; Liang, F.; He, B.; Minch, B.;
Wegner, G. J. Am. Chem. Soc. 2005, 127, 15107–15111.
157.2, 156.6, 144.9, 142.4, 134.9, 134.7, 134.1, 134.0, 133.5, 133.4,
133.3, 133.2, 133.1, 132.1, 132.0, 127.3, 127.2, 126.4, 126.3, 126.0,
125.9, 125.5, 125.4, 124.9, 124.9, 124.8, 124.8, 123.2, 123.1, 123.0,
122.9, 121.3, 120.6, 120.5, 116.5, 116.2, 116.0, 115.9, 115.8, 115.2, 111.3,
56.1, 49.4, 45.2, 31.8, 31.7, 29.6, 29.3, 29.2, 29.0, 28.9, 28.6, 28.5, 27.4,
27.1, 26.9, 26.5, 22.6, 22.5, 22.5, 14.1, 13.9. LR-MS (MALDI-TOF): m/z
1214.0 [MþNa]þ. HRMS (MALDI-FT): Calcd for C69H91N6O7F4:
1191.6880. Found: 1191.6900.
17. Almgren, M. Aust. J. Chem. 2003, 56, 959–970.
4.13. Compound G1
18. (a) Chen, Y.; Lu¨, Y.; Han, Y.; Zhu, B.; Zhang, F.; Bo, Z.; Liu, C.-Y. Langmuir 2009, 25,
8548–8555; (b) Xu, X.-N.; Wang, L.; Li, Z.-T. Chem. Commun. doi:10.1039/
B914030A
19. Petersen, L.; Jensen, K. J. J. Org. Chem. 2001, 66, 6268–6275.
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Hallberg, A. J. Med. Chem. 2006, 49, 6133–6137.
To a stirred solution of C60 (72 mg, 0.10 mmol), iodine (66 mg,
0.20 mmol) and compound 1521 (55 mg, 0.10 mmol) in toluene
(50 mL) was added DBU (34
mL, 0.10 mmol). The solution was
stirred at rt for 4 h and then the solvent removed under
21. Staudinger, B. Makromol. Chem. 1949, 3, 264–270.