Self-assembly of a new series of quadruply hydrogen bonded heterotrimers driven by the donor-acceptor interaction

Article abstract of DOI:10.1016/j.tet.2005.07.075

This paper describes the self-assembly of a new series of heterotrimers in chloroform-d by utilizing the cooperative interaction of hydrogen bonding and donor-acceptor interaction. Compounds 1 and 11, in which an 2-ureido-4[1H]- pyrimidinone unit is conne

Full text of DOI:10.1016/j.tet.2005.07.075

Tetrahedron 61 (2005) 9600–9610
Self-assembly of a new series of quadruply hydrogen bonded
heterotrimers driven by the donor–acceptor interaction
Xiao-Qiang Li,a Mu-Xin Jia,b Xiao-Zhong Wang,a Xi-Kui Jiang,a Zhan-Ting Li,a,
*
c,
Guang-Ju Chenb, and Yi-Hua Yu
*
*
aState Key Laboratory of Bio-Organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bDepartment of Chemistry, Beijing Normal University, Beijing 100875, China
cSchool of Science and Engineering, East China Normal University, Shanghai 200062, China
Received 16 May 2005; revised 22 July 2005; accepted 22 July 2005
Available online 10 August 2005
Abstract—This paper describes the self-assembly of a new series of heterotrimers in chloroform-d by utilizing the cooperative interaction of
hydrogen bonding and donor–acceptor interaction. Compounds 1 and 11, in which an 2-ureido-4[1H]-pyrimidinone unit is connected to 34-
crown-10 or 36-crown-10, were used as donor monomer, and 2 and 19, in which an 2-ureido-4[1H]-pyrimidinone unit is connected to NDI,
were used as acceptor monomer, while linear compound 4, which contains two diamido-1,8-naphthyridines, was used as template. A large
tri-p-(t-butyl)phenylmethoxyl group was introduced to 19 in order to compare its assembling behavior with that of 2. Mixing 4 with dimer
1$2 caused 1$2 to fully decompose and to afford 55% of ‘in–in’-oriented heterotrimer 1$4$2. Adding 4 to the solution of 2$11 or 11$19 in
chloroform-d also led to full dissociation of the dimers. However, in these systems the ‘in–in’-arranged heterotrimer 2$4$11 or 11$4$19
could be produced exclusively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
efficiently in constructing new supramolecular species.
Nevertheless, only recently have examples of supramolecular
assemblies of this kind been reported.7
Cooperative interaction of different non-covalent forces play a
critical role in the formation of biological structures and
functions.1 For example, the DNA double helixes are
stabilized mainly by intermolecular hydrogen bonds between
the complementary bases and stacking interactions between
adjacent base pairs, whereas the secondary and tertiary
structures of proteins are generated as a result of the
cooperative behavior of specifically located hydrogen bonds,
hydrophobic interaction, and Van der Waals force. One of the
challenges in supramoleulcar chemistry is the construction of
new molecular assemblies with defined structures or functions
in a strong, selective, and directional way.2 In the past decade,
a large number of artificial supramolecular architecture have
been constructed based onsingle non-covalent force including
transition metal–ligand interaction,3 hydrophobic inter-
action,4 hydrogen bonding,5 and electrostatic interaction.6 In
principle, the combination of two or more different non-
covalent interactions may also function well or even more
Due to their remarkable stability and directionality, the self-
complimentary 2-ureido-4[1H]-pyrimidinone-based quad-
ruply hydrogen bonded AADD (A, hydrogen bonding
acceptor; D, hydrogen bonding donor) homodimers have
recently found extensive applications in self-assembly of
discrete supramolecular systems.8–10 Previously, we had
reported that AADD-featured homodimers of 1 and 2 could
dissociate to generate more stable quadruply hydrogen
bonded heterodimer 1$2,11,12 as a result of the additional
intermolecular donor–acceptor interaction between the
electron-rich bis(p-phenylene)-34-crown-10 moiety of 1
and the electron-deficient naphthalene diimide (NDI) of 2.13
Moreover, the addition of 3 to the solution of 1$2 in
chloroform-d led to the formation of heterodimers 1$3 and
2$3, both of which possess a new ADDA–DAAD binding
motif.11a The formation of the hydrogen bonded hetero-
dimers from hydrogen bonded homodimers driven by
additional donor–acceptor interaction represents a new
and useful assembling strategy. In this paper we report
that linear compounds incorporating two diamido-1,8-
naphthyridine moieties have been successfully utilized to
Keywords: Hydrogen bonding; Donor–acceptor interaction; Self-assembly;
Heterocycle; Supramolecular chemistry.
*
Corresponding authors. Tel.: C86 21 5492 5122; fax: C86 21 6416
6128; e-mail addresses: ztli@mail.sioc.ac.cn; gjchen@bnu.educ.cn;
yhyu@phy.ecnu.edu.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.075

X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
9601
template the selective self-assembly of a new series of
hydrogen bonded heterotrimers whose structures are
regulated by additional donor–acceptor interaction.14
of 1, 2, and 4 revealed that the length of the linker between
the two binding moieties of 4 is suitable for the formation of
a potential heterotrimer 1$4$2.
The synthetic route for 4 is shown in Scheme 1. Thus,
diamide 7 was first produced from the reaction of 5 and 6
and then hydrolyzed with sodium hydroxide to yield 8.15
Subsequent treatment of 8 with suberoyl chloride in refluxed
THF produced 4, which is of good solubility in organic
solvents such as chloroform and dichloromethane.
2. Results and discussion
Previous investigation has revealed that ADDA–DAAD-
typed heterodimers such as 1$3 and 2$3 are remarkably
more stable than the corresponding AADD–DDAA homo-
dimers.11a In principle, linear molecules (A, Fig. 1)
incorporating two 2,7-diamido-1,8-naphthyridine moieties
connected by a flexible linker of proper length might also
induce the dissociation of heterodimers of monomers B and
C to generate a new generation of heterotrimers (Fig. 1). To
explore this possibility, compound 4 was prepared. The four
n-octyl groups were expected to provide solubility in
common organic solvents. Molecular modeling for a system
Scheme 1.
Prior to binding studies with 4, the ability of 7 to induce the
dissociation of homodimer 9$9 in chloroform-d were
investigated by 1H NMR spectroscopy.16,17 Adding
1 equiv of 7 to the solution of 9 in chloroform-d induced
the homodimer of the latter to fully dissociate and to afford
heterodimer 7$9 exclusively (Fig. 2). The structure of 7$9
has been characterized by using the methods for the
characterization of other similar heterodimers.11a
The binding behaviors of 4 with homodimers 1$1 and 2$2
were then investigated. As revealed by Figure 3b and d,
adding 1 equiv of 4 to the solution of 1 or 2 in CDCl3 also
led to complete dissociation of the latter’s homodimer due
to the formation of new heterotrimers 12$4 and 22$4,
respectively. In principle, the two molecules of 1 or 2 in the
Figure 1. The underlying assembling strategy for the new generation of
heterotrimers driven by cooperative hydrogen bonding and donor–acceptor
interactions.

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X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
9603
chloroform-d. UV–vis experiment afforded an apparent 3
value of 320 cmK1 MK1 (lmaxZ470 nm) for the charge-
transfer absorbance band of the new mixture solution.
Because the 1H NMR spectrum had revealed that there was
no important amount of 1$2 in the solution, this charge-
transfer absorbance band was obviously produced by the
‘in–in’-oriented heterotrimer 1$4$2, which, together with
other isomeric trimers, contributed to the two sets of signals
in Figure 3c. Similar to the above structurally similar
heterotrimers, trimer 1$4$2 should also be mixtures of four
possible isomers, depending on the orientation of 1 and 2
relative to 4. Reducing the solution temperature to K20 8C
led to the NH signals to split (Fig. 3e). Although these
signals could not be definitely assigned to either of the
heterotrimers, this observation revealed that, besides the
‘in–in’-oriented 1$4$2, other isomeric heterotrimers might
also exist in the solution and at the lowered temperature, the
exchange of the monomers among the different trimers
Figure 2. Partial 1H NMR spectra (400 MHz, 5.0 mM) in CDCl3 at 25 8C:
(a) 9; (b) 7C9 (1:1); (c) 7. For signal numbering, see the structures in the
text.
1
became slow on the H NMR time scale.
1
Because the above H NMR and UV–vis results could not
be utilized to determine the percentage of the ‘in–in’-
oriented heterotrimer 1$4$2, compound 10 was prepared
from 8 and docanoyl chloride in refluxed THF (Scheme 2).
Adding 2 equiv of 10 to the solution of 1$2 in chloroform-d
induced the heterodimer to partially dissociate as a result of
the formation of heterodimers 1$10 and 2$10, which gave
rise to two sets of new signals at 14.21, 11.51, 9.72 and
13.85, 11.28, 10.12 ppm, respectively, in the 1H NMR
spectrum. Although only one set of signals was displayed
for each of them, in principle both 1$10 and 2$10 should
also be mixtures of two isomeric dimers. Figure 3h shows
1
Figure 3. Partial 1H NMR (400 MHz) spectra in CDCl3 at 25 8C: (a) 1
(6.0 mM); (b) 12$4 ([4]Z3.0 mM); (c) 1$2$4 ([4]Z6.0 mM); (d) 22$4
([4]Z3.0 mM); (e) 1$2$4 ([4]Z6.0 mM) at K20 8C; (f) 2; (g) 1$2; (h) 1C
2C10 (12 mM) ([1]Z[2]Z6.0 mM).
the partial H NMR spectrum of the 1:1:2 solution of 1, 2,
and 10 in chloroform-d. Based on the relative integrated
intensity of the H-1 signals of 1$10 and 2$10, we
determined the yields of both 1$10 and 2$10 to be
approximately 44%, which implied approximately 44%
dissociation of 1$2 in the tri-component solution. Because
the linker between the two heterocyclic moieties of 4 is not
short, it should be acceptable to assume that the DAAD–
ADDA motifs of dimers 1$10 and 2$10 and all possible
trimers 12$4, 22$4, and 1$4$2 should possess comparable
stability when the donor–acceptor interaction in the ‘in–in’-
oriented 1$4$2 was not considered. Quantitative dis-
sociation of 1$2 in the 1:1:1 solution of 1, 2, and 4 in
chloroform-d suggested that at least 56% of ‘in–in’-oriented
1$4$2 was formed as a result of the additional donor–
acceptor interaction between the electron-rich cyclophane
unit of 1 and the electron-deficient NDI unit of 2.18
trimers should have three possible arranging patterns, that
is, the ‘in–in’, ‘in–out’, and ‘out–out’-orientations for the
cyclophane unit of 1 or the NDI unit of 2 relative to 4. The
fact that only one set of new signals were displayed in both
systems implies that the exchange of the monomers among
the possible trimeric isomers was fast on the NMR time
scale. Intermolecular NOE effect was observed for both
trimers. The facts that 1$1 and 2$2 were not formed in the
mixture solution also implied that trimers 12$4 and 22$4
were formed quantitatively.
When 1 equiv of 4 was added to 1 equiv of the 1:1 solution
of 1 and 2 in chloroform-d, the highly stable heterodimer
1$2 was also fully decomposed (Fig. 3c and g). The H
1
NMR spectrum revealed two sets of NH signals at 14.11,
11.44, 9.71 ppm and 13.78, 11.21, 10.09 ppm, respectively,
which could be easily assigned to those of the binding
moiety that exists in 12$4 or 22$4 by comparing Figure 3c
with Figure 3b and d and also by adding 12$4 or 22$4 to the
solution, which caused the corresponding signals to
increase. NOESY experiment revealed intermolecular
connections (see the structures of the trimers), which is
also consistent with the DAAD–ADDA motif of the trimers.
The identical result was obtained when 1 equiv of the 2:1
solution of 1 and 4 to 1 equiv of the 2:1 solution of 2 and 4 in
Scheme 2.
It is well-established that 1,5-dialkoxynaphthalene (DAON)
is a stronger electron donor than 1,4-dialkoxybenzene for
supramolecular self-assembly.13,19 Therefore, it was
envisioned that replacement of the 1,4-dialkoxybenzene
unit of 1 with the DAON unit would produce a compound

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X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
with a stronger electron-donating ability than 1. Such a
compound might lead to more selective formation of more
stable heterotrimers similar to 1$4$2. Therefore, compound
11 was synthesized as outline in Scheme 3. In brief, 12 was
first reacted with 13 in refluxed acetonitrile to produce
cyclophane 14. The Heck reaction of 14 with 15 in hot
pyrrolidine yielded 16, which was then de-protected with
sodium hydroxide to afford 17. Finally, a palladium(II)-
catalyzed reaction of 17 with 18 in THF yielded 11 in 31%
yield.
2$4$11, 22$4, and 112$4 by using the methods described
above for other tri-component systems. The orange color of
the solution did not change substantially after 11 was added,
and UV–vis experiment gave an apparent 3 value of
850 MK1 cmK1 (lmaxZ487 nm) for the charge-transfer
1
absorbance band. Since the H NMR study revealed that
there was no detectable amount of dimer 2$11 in the tri-
component solution, this absorbance band should be
produced exclusively by the ‘in–in’-arranged heterotrimer
2$4$11.
Adding 2 equiv of 10 to 1 equiv of the solution of
heterodimer 2$11 in chloroform-d induced the dimer to
partially decompose as a result of the formation of
heterodimers 2$10 and 10$11 (vide supra) (Fig. 4a and d).
Based on the integrated intensity of the H-1 signals of the
dimers, we determined the yields of dimers 2$10 and 10$11
to be approximately 12%. If the additional donor–acceptor
interaction in the ‘in–in’-arranged trimer 2$4$11 were not
considered, it should be reasonable to assume that the
ADDA–DAAD binding motif in dimers 2$10 and 10$11 and
all possible trimers 2$4$11, 22$4, and 112$4 should be
1
comparable. The above H NMR result suggested that at
least 88% of ‘in–in’-oriented trimer 2$4$11 was formed in
the 1:1:1 solution of 2, 4, and 11 in CDCl3 due to the
additional intermolecular donor–acceptor interaction
between 2 and 11.
As expected, mixing 1 equiv of 11 with 1 equiv of 2 in
chloroform-d caused complete dissociation of homodimers
11$11 and 2$2 and led to the formation of heterodimer 2$11
exclusively (Fig. 4d–f). The structure of heterodimer 2$11
had been determined by using the methods reported
previously for dimer 1$2.11a The solution turned to dark
orange as a result of the strong intermolecular donor–
acceptor interaction between the cyclophane unit of 11 and
the NDI unit of 2. UV–vis experiment afforded a 3 value of
1020 MK1 cmK1 (lmaxZ488 nm) for the charge-transfer
absorbance band of dimer 2$11. This value is substantially
Different from the observation that the NH protons split at
lowered temperature (K20 8C) (Fig. 3e), reducing the
temperature to K25 8C did not lead to the 1H NMR signals
of the 1:1:1 mixture solution of compounds 2, 4, and 11 to
split in chloroform-d. Because compounds 1 and 11 possess
the same binding unit, heterotrimers of the same skeleton
generated from them with 2 and 4 should have very close
stability except the ‘in–in’-oriented heterotrimers 1$4$2 and
2$4$11, in which the additional donor–acceptor interaction
existed. Therefore, the above observation suggested that the
‘in–in’-oriented heterotrimer 2$4$11 was actually formed
exclusively at least at the low temperature of K20 8C
(R97% considering the sensitivity of the 1H NMR method).
larger than that of dimer 1$2 (429 MK1 cmK1, lmax
Z
475 nm),11a indicative of the higher stability of 2$11
compared to 1$2. 1H NMR dilution experiments in
CDCl3–DMSO-d6 (4%) derived a binding constant of ca.
2.1!105 MK1 for dimer 2$11.11a The value is significantly
larger than that of dimer 1$2 (3.7!104 MK1),11a which is
consistent with the above UV–vis result.
Further evidence to support the selective formation of the
‘in–in’-oriented heterotrimer 2$4$11 came from the 1H
NMR and UV–vis studies of the system of 4, 11, and 19. A
large tri-p-(t-butyl)phenylmethoxyl group was introduced in
19 in order to reduce the exchanging rate between the
threaded pseudorotaxane-styled trimeric isomer and all
other possible isomers, because such a large group could not
The addition of 1 equiv of 4 to the solution of heterodimer
2$11 in chloroform-d led to the signals of the heterodimer to
disappear in the 1H NMR spectrum (Fig. 4c). Similar to the
system of 1, 2, and 4 (Fig. 3), two new sets of NH signals
were also displayed at 14.13, 11.46, 9.70 ppm and 13.82,
11.26, 10.10 ppm, respectively. These signals were assigned
to those of the two binding moieties in heterotrimers

X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
9605
be de-threaded from the cavity of the cyclophane of 11.20
The synthesis of 19 is shown in Scheme 4. In brief, 22 was
first prepared from the reaction of 20 and 21 in hot DMF and
then hydrolyzed with hydrazine to produce 23. Treatment of
23 with 24 and 25 in hot DMF yielded 26, which was then
converted into 27 in refluxed thionyl chloride. Finally,
compound 27 was reacted with 28 in hot chloroform to
afford 19 in 28% yield.
As expected, heterotrimer 4$192 (vide supra) was generated
exclusively when adding 1 equiv of 14 to 2 equiv of 19 in
chloroform-d (Fig. 5a and b), and heterodimer 11$19 was
also formed quantitatively in the 1:1 mixture solution of 11
and 19 in chloroform-d. The structure of dimmer 11$19 was
supported by the NOESY spectrum, which revealed
intermolecular NOEs between the NH signals as shown in
the structure. Different from that of dimer 2$11, which
revealed a single signals at 8.40 ppm for the four protons of
1
the NDI unit (Fig. 4d), the H NMR spectrum of 11$19
revealed two sets of doublets (8.56, 8.50, 8.43, and
8.34 ppm) for the NDI protons as a result of the increased
shielding effect of the cyclophane unit of 11 (Fig. 5d).
Moreover, lowering the solution temperature to K35 8C did
not cause the NH signals of the dimer to split. By using the
1H NMR dilution method, we determined the Ka of 11$19 in
chloroform-d and DMSO-d6 (4%) to be ca. 2.2!105 MK1
,
which is very close to that of dimer 2$11 in the same
solvent. The solution of dimer 11$19 in chloroform-d
displayed a dark orange color as a result of the strong
intermolecular donor–acceptor interaction and UV–vis
study afforded an apparent 3 value of 880 MK1 cmK1
.
This value was independent of concentration (0.5–50 mM)
and also comparable to that of dimer 2$11. All these
observations indicated that the NDI moiety of 19 was
completely threaded through the cavity of the cyclophane of
11 and 11$19 existed as a stable pseudo[2]rotaxane.
Scheme 3.
Adding 2 equiv of 10 to the solution of dimer 11$19 in
chloroform-d caused approximately 15% of the dimer to
dissociate and to afford new heterodimers 10$11 and 10$19
(vide supra) as indicated by the 1H NMR spectrum (Fig. 5f).
In contrast, addition of a small excess of 4 to a solution of
dimer 11$19 in chloroform-d caused the NH signals of the
dimer to disappear, and two sets of NH signals at 14.15,
11.46, 9.70 ppm and 13.82, 11.25, 10.11 ppm, respectively,
Figure 4. Partial 1H NMR (400 MHz, 4.0 mM) spectra in CDCl3 at 25 8C:
(a) 2C11C10 (1:1:2); (b) 2C4 (2:1, [4]Z2.0 mM); (c) 2C4C11 (1:1:1);
(d) 2C11 (1:1); (e) 4C11 (1:2, [4]Z2.0 mM); (f) 11; (g) 2.

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X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
Scheme 4.
splitting at the temperature of RK20 8C, as observed above
for the solution of compounds 1, 2, and 4 in chloroform-d.
Different from those of dimers 2$11 and 11$19, the NOESY
spectrum of the 1:1:1 solution of 2, 4, and 11 or 4, 11, and 19
in chloroform-d did not reveal any intermolecular NOEs
between the NH signals of the 2-ureido-4-pyrimidinone
units. This observation is also consistent with the formation
of heterotrimers 2$4$11 and 11$4$19 in the solution. In
addition, vapor pressure osmometry (VPO) in chloroform–
toluene (85:15 v:v) at 30 8C gave average molecular masses
of 2400 (G300 u) and 2800 (G400 u) for the two systems,
which was also in agreement with the formation of the two
heterotrimers, whose calculated masses are 2620 and 3150,
respectively. A energy-minimized structure of heterotrimer
2$4$11 has been obtained and is shown in Figure 6, which
reveals a triangle skeleton for the trimer due to the
intermolecular hydrogen bonding and donor–acceptor
interactions.
Figure 5. Partial 1H NMR (400 MHz) spectra in CDCl3 at 25 8C: (a) 19
(4.0 mM); (b) 4C19 (1:2, [4]Z2.0 mM); (c) 4C11 (1:2 [11]Z4.0 mM);
(d) 11C19 (1:1, 4.0 mM); (e) 4C11C19 (1:1:1, 4.0 mM); (f) 10C11C19
(1:1:2, [10]Z4.0 mM).
were displayed. The result is very similar to that observed
for the system of 2, 4, and 11, indicating the formation of
new heterotrimers 11$4$19 (vide supra). The 1H NMR
spectrum did not exhibit new signals at the low temperature
of K25 8C. In principle, the existence of the large tri-p-(t-
butyl)phenylmethoxyl group in 19 would greatly slow down
the exchanging processes between the ‘in–in’-oriented
heterotrimer 11$4$19 and any other possible trimers.20
The above results clearly showed that there were no
important amount of other kinds of heterotrimers in the
tri-component solution, because such possible exchange
processes, if existing, would be revealed by the NH signal
Figure 6. Energy-minimized structures of dimers 2$4$11. All the side
chains of the monomers are replaced with methyl groups for clarity.

X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
9607
3. Conclusion
(300 mL) was added and the insoluble solid was filtered
off. The filtrate was washed with water, brine, and dried.
After the solvent was removed in vacuo, the crude product
was chromatographed (CH2Cl2/MeOH 50:1) to give 4 as a
yellow solid (0.22 g, 49%). Mp 156–158 8C. 1H NMR
(CDCl3): d 0.84 (t, JZ6.9 Hz, 12H), 1.22–1.54 (m, 52H),
1.63–1.75 (m, 12H), 2.27–2.30 (m, 2H), 2.46 (t, JZ7.2 Hz,
4H), 8.11 (d, JZ9.0 Hz, 4H), 8.44 (t, JZ8.4 Hz, 4H), 8.65
(s, 4H). 13C NMR (CDCl3): d 14.1, 22.7, 24.7, 27.6, 28.6,
29.3, 29.5, 29.7, 31.8, 33.0, 37.6, 49.3, 113.7, 118.3, 139.0,
139.1, 154.0, 154.0, 172.8, 175.8. IR (cmK1): n 3421, 3307,
2926, 2855, 1708, 1689, 1610, 1388, 1286, 1136, 855, 803.
MALDI-HRMS: m/z: 991.7435, [MCH]C. Calcd for
C60H94N8O4: 991.7471.
We have reported the self-assembly of a new class of
heterotrimers in chloroform by making use of both the
quadruply hydrogen bonding and the donor–acceptor
interaction as the driving forces. The effect of the structure
of the monomers on the self-assembling selectivity of the
new series of heterotrimers has been investigated. Strong
ADDA–DAAD quadruply hydrogen bonding has been used
to ‘glue’ three discrete components together, whereas
additional intermolecular donor–acceptor interaction
makes the components arrange in order. As a result,
among other nine possible heterotrimers, one special
heterotrimer has been selectively assembled from
elaborately designed monomer molecules. The results
demonstrate the great potential of the cooperative inter-
action between different co-valent forces for assembling
new kind of supramolecular architectures.
4.1.4. Compound 9. This compound was prepared from
2-amino-4-hydroxy-6-methylpyrimidine and n-octyl iso-
cyanate (97%) as a white solid following the reported
procedure for preparation of a similar compound.8 Mp 171–
1
173 8C. H NMR: d 0.86 (t, JZ6.6 Hz, 3H), 1.25–1.30 (m,
4. Experimental
10H), 1.54–1.61 (m, 2H), 2.22 (s, 3H), 3.20–3.26 (m, 2H),
5.81 (s, 1H), 10.13 (s, 1H, NH), 11.85 (s, 1H, NH), 13.14 (s,
1H, NH). MS (EI): m/z: 280 [MC]. Elemental Anal. Calcd
(%) for C14H24N4O2 (280.37): C, 59.98; H, 8.63; N, 19.98.
Found: C, 59.84; H, 8.60; N, 19.97.
4.1. General procedure. See Ref. 11a
4.1.1. Compound 7. To a suspension of 6 (0.72 g,
4.50 mmol), NEt3 (2.00 mL) and DMAP (50 mg) in
chloroform (300 mL) was added a solution of 521 (2.95 g,
9.90 mmol) in chloroform (25 mL). The mixture was stirred
under reflux for 4 h and then cooled. The insoluble materials
were filtered off and the filtrate was washed with dilute
hydrochloric acid, saturated NaHCO3 solution, water, brine,
and dried over sodium sulfate. After the solvent was
removed, the crude product was purified by column
chromatography (hexane/dichloromethane 5:1–1:2) to
4.1.5. Compound 10. To a stirred solution of 8 (0.30 g,
0.70 mmol), NEt3 (1 mL), and DMAP (50 mg) in CHCl3
(20 mL) was added a solution of docanoyl chloride (0.22 g,
1.0 mmol) in CHCl3 (5 mL). The solution was then stirred
under reflux for 14 h. After work-up, the crude product was
subjected to flash chromatography (CH2Cl2) to give 10 as a
white solid (0.30 g, 73.5%). Mp 133–134 8C. 1H NMR
(CDCl3): d 0.83–0.89 (m, 9H), 1.23–1.26 (m, 36H), 1.47–
1.56 (m, 2H), 1.64–1.80 (m, 4H), 2.25–2.29 (m, 1H), 2.46 (t,
JZ7.5 Hz, 2H), 8.12–8.15 (m, 4H), 8.45 (t, JZ6.3 Hz, 2H).
13C NMR (CDCl3): d 14.1, 22.7, 25.3, 27.6, 29.2, 29.3, 29.3,
29.4, 29.7, 31.9, 31.8, 33.1, 38.0, 49.4, 113.5, 113.6, 118.4,
139.0, 153.9, 154.0, 172.5, 175.6. IR (cmK1): n 3310, 2925,
2854, 1689, 1610, 1506, 1288, 1136, 854, 802. MALDI-MS:
m/z: 581 [MCH]C. Elemental Anal. Calcd (%) for
C36H60N4O2 (580.89): C, 74.44; H, 10.41; N, 9.64. Found:
C, 74.66; H, 10.51; N, 9.62.
1
afford compound 7 as a yellowish oil (2.10 g, 67%). H
NMR (CDCl3): d 0.82–0.86 (m, 12H), 1.23–1.28 (m, 48H),
1.46–1.55 (m, 4H), 1.64–1.74 (m, 4H), 2.29–2.35 (m, 2H),
8.13 (d, JZ9.0 Hz, 2H), 8.48 (d, JZ8.7 Hz, 2H), 8.70 (s,
4H). MALDI-HRMS: m/z: 693.6020 [MCCH]. Calcd for
C44H76N4O2: 693.6041.
4.1.2. Compound 8. A solution of 7 (1.25 g, 1.80 mmol)
and NaOH (0.30 g) in ethanol (20 mL) and water (4 mL)
was heated under reflux for 4 h and then concentrated in
vacuo. The residue was triturated with dichloromethane
(250 mL). The organic phase was washed with water, brine,
and dried over magnesium sulfate. After the solvent was
removed, the crude product was purified by column
chromatography (CH2Cl2/MeOH 20:1) to obtain 8 as a
white solid (0.57 g, 75%). Mp 197–198 8C. 1H NMR
(CDCl3): d 0.82–0.89 (m, 6H), 1.28–1.39 (m, 24H), 1.43–
1.56 (m, 2H), 1.64–1.73 (m, 2H), 2.26–2.32 (m, 1H), 5.45
(s, 2H), 6.66 (d, JZ8.4 Hz, 1H), 7.81 (d, JZ8.7 Hz, 1H),
7.94 (d, JZ9.0 Hz, 1H), 8.27 (d, JZ9.0 Hz, 1H), 8.57 (s,
1H). MALDI-MS: m/z: 427 [MCH]C. Elemental Anal.
Calcd (%) for C26H42N4O (426.64): C, 73.20; H, 9.92; N,
13.13. Found: C, 73.30; H, 9.97; N, 13.04.
4.1.6. Compound 14. To a stirred suspension of 1213a
(7.30 g, 11.4 mmol), K2CO3 (13.0 g, 94.2 mmol) and NaI
(2.00 g, 13.3 mmol) in MeCN (200 mL) was added a
solution of 1322 (2.15 g, 11.4 mmol) in MeCN (20 mL).
The reaction mixture was then heated at 80 8C for 24 h and
cooled. The solid was filtered off and washed with AcOEt.
The combined filtrate was concentrated in vacuo and the
resulting residue triturated with AcOEt (200 mL). The
organic phase was washed with water, brine, and dried.
Upon removal of the solvent, the oily residue was purified
by column chromatography (EtOAc/CH3OH 50:1) to afford
14 as a yellow solid (2.66 g, 35%). Mp 98–100 8C. 1H NMR
(CDCl3): d 3.65–3.86 (m, 24H), 3.98–4.01 (m, 4H), 4.20–
4.24 (m, 4H), 6.48 (d, JZ1.5 Hz, 2H), 6.74 (d, d, J1Z
3.0 Hz, J2Z7.2 Hz, 2H), 6.94 (d, JZ0.9 Hz, 1H), 7.26–7.29
(m, 2H), 7.85 (d, d, J1Z2.7 Hz, J2Z8.4 Hz, 2H). EI-MS: m/z:
664 [M]C. Elemental Anal. Calcd (%) for C32H41BrO10
(665.57): C, 57.75; H, 6.21. Found: C, 57.77; H, 6.27.
4.1.3. Compound 4. To a stirred suspension of 8 (0.43 g,
1.00 mmol) and Cs2CO3 (0.50 g, 1.56 mmol) in THF
(40 mL) was added a solution of suberoyl chloride
(91 mg, 0.45 mmol) in THF (5 mL). The mixture was
refluxed for 12 h and then concentrated. Chloroform

9608
X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
4.1.7. Compound 16. To a solution of 14 (0.33 g,
0.50 mmol) in pyrrolidine (4 mL) were added Pd(PPh3)4
(30.0 mg, 0.040 mmol, 8%) and 15 (65.0 mg, 0.75 mmol).
The mixture was stirred at 80 8C for 4 h and then
concentrated in vacuo. The resulting residue was triturated
with CH2Cl2 (50 mL). The organic phase was washed with
hydrochloric acid, water, brine, and dried. After the solvent
was removed, the crude product was purified by column
chromatography (EtOAc/CH3OH 50:1) to obtain 16 as a
yellow solid (0.29 g, 85%). Mp 95–96 8C. 1H NMR
(CDCl3): d 1.57 (s, 6H), 3.69–3.89 (m, 24H), 3.98–4.01
(m, 4H), 4.17–4.25 (m, 4H), 4.48 (d, JZ9.0 Hz, 1H), 6.61
(d, d, J1Z3.0 Hz, J2Z9.0 Hz, 1H), 6.67 (d, JZ8.1 Hz, 1H),
6.73–6.75 (m, 2H), 724–7.28 (m, 2H), 7.83 (d, d, J1Z
3.0 Hz, J2Z8.1 Hz, 2H). EI-MS: m/z: 668 [M]C. Elemental
Anal. Calcd (%) for C37H48O11 (668.77): C, 66.45; H, 7.23.
Found: C, 66.59; H, 7.08.
114.6, 116.7, 118.2, 125.2, 125.2, 126.7, 151.5, 152.4,
152.8, 153.8, 154.3, 156.5, 170.4. IR (cmK1): n 3211, 2926,
2855, 1697, 1594, 1264, 1080, 768. MALDI-HRMS: m/z:
911.4406 [MC Na]C. Calcd for C48H64N4O12: 911.4413.
4.1.11. Compound 22. A solution of 2024 (1.04 g,
2.00 mmol), 2125 (0.74 g, 2.00 mmol), K2CO3 (1.10 g,
8.00 mmol), and KI (0.10 g) in DMF (20 mL) was stirred
at 80 8C for 12 h and then cooled. The insoluble materials
were filtered off and the solvent was removed under reduced
pressure. The residue was triturated with AcOEt (150 mL).
The organic phase was washed with aqueous HCl solution,
NaHCO3 solution, water, brine, and dried (Na2SO4). After
the solvent was removed in vacuo, the crude product was
recrystallized from AcOEt to obtain 22 (1.44 g, 90%) as a
white solid. Mp 154–156 8C. 1H NMR (CDCl3): d 1.26–1.36
(m, 39H), 1.65–1.77 (m, 4H), 3.67 (t, JZ7.2 Hz, 2H), 3.91
(t, JZ6.9 Hz, 2H), 6.75 (d, JZ7.8 Hz, 2H), 7.05–7.09 (m,
8H), 7.21–7.26 (m, 6H), 7.70–7.71 (m, 2H), 7.82–7.84 (m,
2H). MALDI-MS: m/z: 812 [MC Na]C. Elemental Anal.
Calcd (%) for C55H67NO3$0.25H2O (794.64): C, 83.13; H,
8.58; N, 1.76. Found: C, 83.31; H, 8.54; N, 1.33.
4.1.8. Compound 17. To a solution of 16 (0.29 g,
0.43 mmol) in benzene (10 mL) was added NaOH
(52.0 mg, 1.30 mmol). The mixture was refluxed for 4 h,
cooled and washed with water, brine, and dried. After the
solvent was removed in vacuo, the residue was chromato-
graphed (EtOAc/CH3OH 50:1) to afford 17 as a white solid
4.1.12. Compound 23. Hydrazine hydrate (2.0 mL, 85%)
was added to a solution of 22 (1.10 g, 1.40 mmol) in ethanol
(30 mL). The solution was refluxed for 3 h and then
concentrated in vacuo to give a residue, which was triturated
with chloroform (100 mL). The organic phase was washed
with water, brine, and dried (NaSO4). After removal of the
solvent under reduced pressure, the crude product was
recrystallized from AcOEt to afford compound 23 as a white
1
(0.26 g, 98%). Mp 92–93 8C. H NMR (CDCl3): d 3.21 (s,
1H), 3.67–3.92 (m, 24H), 3.97–4.01 (m, 4H), 4.21–4.25 (m,
4H), 4.48 (d, JZ9.0 Hz, 1H), 6.56 (d, d, J1Z3.0 Hz, J2Z
9.0 Hz, 1H), 6.75 (d, d, J1Z3.3 Hz, J2Z7.8 Hz, 2H), 6.82
(d, JZ2.7 Hz, 1H), 728–7.29 (m, 2H), 7.85 (d, d, J1Z
2.4 Hz, J2Z8.1 Hz, 2H). EI-MS: m/z: 610 [M]C. Elemental
Anal. Calcd (%) for C34H42O10 (610.69): C, 66.87; H, 6.93.
Found: C, 66.90; H, 6.89.
1
solid (0.90 g, 91%). Mp 94–96 8C. H NMR (CDCl3): d
1.26–1.43 (m, 39H), 1.73–1.78 (m, 4H), 2.68 (t, JZ7.2 Hz,
2H), 3.92 (t, JZ6.6 Hz, 2H), 6.75 (d, JZ9.0 Hz, 2H), 7.06–
7.10 (m, 8H), 7.21–7.26 (m, 6H). ESI-MS: m/z: 610 [MC
H]C. Elemental Anal. Calcd (%) for C47H65NO$0.25H2O
(664.54): C, 84.94; H, 9.96; N, 2.11. Found: C, 84.99; H,
9.98; N, 1.55.
4.1.9. Compound 18. A solution of 2-amino-5-iodo-6-
methyl-3H-pyrimidin-4-one23 (3.00 g, 12.0 mmol) and n-n-
octyl isocyanate (2 mL) in THF (200 mL) was heated under
reflux for 24 h. After work-up,11a the crude product was
purified by column chromatography (CH2Cl2/MeOH 30:1)
to afford 18 (3.50 g, 73%) as a white solid. Mp 150–152 8C.
1H NMR (CDCl3): d 0.85–0.88 (m, 3H), 1.27–1.32 (m,
10H), 1.58–1.62 (m, 2H), 2.45 (s, 3H), 3.26 (m, 2H), 9.83 (s,
1H), 11.66 (s, 1H), 13.44 (s, 1H). EI-MS: m/z: 406 [MC].
Elemental Anal. Calcd (%) for C14H23IN4O2 (406.27): C,
41.39; H, 5.71; N, 13.79. Found: C, 41.30; H, 5.71; N, 13.52.
4.1.13. Compound 26. A solution of compounds 23 (0.45 g,
0.68 mmol), 24 (0.18 g, 0.68 mmol), and 25 (0.05 g,
0.68 mmol) in DMF (10 mL) was stirred at 120 8C for 4 h.
Upon cooling, the insoluble materials were filtered off and
the solvent was removed in vacuo. The resulting residue was
triturated in chloroform (50 mL) and the solution was
washed with water, brine, and dried (MgSO4). The solvent
was then removed and the crude product purified by column
chromatography (CH2Cl2/MeOH 50:1) to give 26 as a pink
4.1.10. Compound 11. A suspension of 17 (0.31 g,
0.50 mmol), 18 (0.31 g, 0.77 mmol), Pd(PPh3)2Cl2 (30 mg,
6%), and CuI (10 mg, 10%) in THF (10 mL) and NEt3
(1.5 mL) was stirred at rt for 5 h and then concentrated
under reduced pressure. The residue was triturated with
CH2Cl2 (50 mL). After work-up, the resulting residue was
purified by column chromatography (CH2Cl2/CH3OH 20:1)
to produce 11 (0.14 g, 31%) as a yellow solid. Mp 150–
1
solid (0.17 g, 25%). Mp 242–243 8C. H NMR (CDCl3): d
1.25–1.39 (m, 39H), 1.71–1.75 (m, 4H), 3.91 (t, JZ6.6 Hz,
2H), 4.19 (t, JZ7.2 Hz, 2H), 5.00 (s, 2H), 6.75 (d, JZ
8.4 Hz, 2H), 7.05–7.09 (m, 8H), 7.22 (d, JZ8.7 Hz, 6H),
8.78 (s, 4H). MALDI-MS: m/z: 989 [MC Na]C. Elemental
Anal. Calcd (%) for C63H70N2O7 (967.24): C, 78.23; H,
7.29; N, 2.90. Found: C, 78.45; H, 7.01; N, 2.76.
1
152 8C. H NMR CDCl3): d 0.84 (t, JZ6.6 Hz, 3H), 1.23–
1.28 (m, 12H), 2.49 (s, 3H), 3.22–3.29 (m, 2H), 3.65–3.84
(m, 24H), 3.96–4.02 (m, 4H), 4.21–4.23 (m, 4H), 6.35 (d,
JZ9.0 Hz, 1H), 6.56 (d, d, J1Z3.3 Hz, J2Z9.0 Hz, 1H),
6.71–6.78 (m, 2H), 6.95 (d, JZ3.3 Hz, 1H), 7.26–7.29 (m,
2H), 7.84 (d, d, J1Z2.1 Hz, J2Z8.7 Hz, 2H), 10.13 (t, JZ
5.1 Hz, 1H), 11.83 (s, 1H), 13.45 (s, 1H). 13C NMR
(CDCl3): d 14.2, 18.7, 22.7, 27.0, 29.3, 29.4, 29.6, 29.7,
31.9, 40.2, 53.2, 68.0, 68.5, 69.7, 69.7, 69.8, 70.6, 70.8,
70.9, 71.0, 71.1, 93.7, 104.3, 105.6, 105.7, 113.1, 113.4,
4.1.14. Compound 19. A suspension of 26 (0.28 g,
0.29 mmol) in thionyl chloride (5 mL) was refluxed for
6 h and then concentrated in vacuo to afford compound 27
as an oil, which was used directly for next step. To a stirred
solution of 2811a (94 mg, 0.29 mmol), triethylamine
(0.8 mL) and DMAP (10 mg) in CHCl3 (15 mL) was
added a solution of the above 27 in chlroform (5 mL). The

X.-Q. Li et al. / Tetrahedron 61 (2005) 9600–9610
9609
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2. (a) Vogtle, F. Supramolecular Chemistry: An Introduction;
Wiley: Chichester, UK, 1991. (b) Lehn, J.-M. Supramolecular
Chemistry: Concepts and Perspectives; VCH: Meinheim,
1995. (c) Schneider, H.-J.; Yatsimirsky, A. Principles and
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mixture was heated under reflux for 36 h, cooled, washed
with water, brine, and dried (MgSO4). The solvent was
removed and the residue was subjected to flash chromato-
graphy (CH2Cl2/MeOH 50:1) to afford 19 as a pink solid
(104 mg, 28%). Mp 212–214 8C. 1H NMR (CDCl3): d 0.84
(t, JZ6.9 Hz, 3H), 1.24–1.67 (m, 57H), 2.49 (t, JZ8.1 Hz,
2H), 3.57–3.59 (m, 2H), 3.98 (t, JZ7.2 Hz, 2H), 4.16 (t, JZ
8.4 Hz, 2H), 4.40 (t, JZ5.4 Hz, 2H), 5.02 (s, 2H), 5.82 (s,
1H), 6.73–6.76 (m, 2H), 7.04–7.09 (m, 8H), 7.20–7.25 (m,
6H), 8.70 (s, 4H), 10.44 (t, JZ3.6 Hz, 1H), 11.76 (s, 1H),
12.97 (s, 1H). 13C NMR (CDCl3): d 14.1, 22.7, 26.2, 27.0,
27.1, 28.1, 29.0, 29.2, 29.3, 29.4 (d), 29.5 (d), 29.6, 31.4,
31.8, 32.7, 34.3, 34.3, 38.7, 41.1, 41.8, 63.0, 63.9, 67.8,
106.0, 112.9, 124.0, 124.2, 126.1, 126.7, 126.8, 126.9,
130.6, 130.7, 130.8, 131.2, 132.2, 139.3, 143.6, 144.2,
148.3, 148.5, 152.5, 154.3, 156.8, 156.9, 162.4, 162.6,
167.6, 172.9. IR (cmK1): n 3040, 2959, 2928, 2856, 1757,
1709, 1672, 1584, 1246, 823, 771. MALDI-MS: m/z: 1273
3. (a) Sauvage, J.-P. Transition Metals in Suparamolecular
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[MCCH].
Elemental
Anal.
Calcd
(%)
for
C79H96N6O9$0.25H2O (1278.15): C, 74.23; H, 7.63; N,
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6.58. Found: C, 74.09; H, 7.70; N, 6.34.
4.2. Vapor pressure osmometry (VPO)
The VPO experiments were performed in chloroform–
toluene (85:15 v:v) at 30 8C with a Knauer-K-700
osmometer, with a synthetic amide (MW: 1772) used for
calibration. Reported results represent single experimental
runs.
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4.3. Binding constants
Measurement of binding constants has been described in the
previous paper.11a
7. (a) Amabilino, D. B.; Dietrich-Buchecher, C. O.; Livoreil, A.;
4.4. Computational method
´
´
Perez-Garcıa, L.; Sauvage, J.-P.; Stoddart, J. F. J. Am. Chem.
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J. A. J. M.; Hirschberg, J. H. K. K.; Sijbesma, R. P.; Meijer,
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Cary, J. M.; Moore, J. S. Org. Lett. 2002, 4, 4663–4666. (f)
Yang, X.; Brown, A. L.; Furukawa, M.; Li, S.; Gardinier,
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Gong, B. Chem. Commun. 2003, 56–57.
The binding pattern was constructed by using the Builder
program within the package HyperChem. Then they were
optimized by the conjugate gradient with the AMBER force
field and the RMS derivative criteria of 0.00001 kcal molK1
.
In order to explore lower-energy conformation on the
potential energy surface, molecular dynamics calculations
were performed with constraint of hydrogen bonds at ca.
˚
2.15 A. After 100 ps molecular dynamics simulation, an
additional round of energy minimization was again
completed.
8. Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.;
Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761–6769.
Acknowledgements
´
´
9. (a) Gonzalez, J. J.; Gonzalez, S.; Priego, E. M.; Luo, C.; Guldi,
D. M.; de Mendoza, J.; Martin, N. Chem. Commun. 2001,
163–164. (b) Rieth, L. R.; Eaton, R. F.; Coates, G. W. Angew.
Chem., Int. Ed. 2001, 40, 2153–2156. (c) Rispens, M. T.;
This work was supported by the Ministry of Science and
Technology (No. G2000078101) and the National Natural
Science Foundation of China.
´
Sanchez, L.; Knol, J.; Hummelen, J. C. Chem. Commun. 2001,
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