Self-assembly and characterization of a giant metallocycle

Article abstract of DOI:10.1016/j.tetlet.2005.02.048

A giant, 100-membered metallocycle 3 was prepared via coordination bond-based self-assembly from W-shaped ligand 9 and a palladium complex. Metallocycle 3 may create three topologically discrete subcavities, thus capable of binding up to three molecules o

Full text of DOI:10.1016/j.tetlet.2005.02.048

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2433–2436
Self-assembly and characterization of a giant metallocycle
Hye-Young Jang, Sung-Youn Chang, Kyoung-Jin Chang and Kyu-Sung Jeong*
Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
Received 21 January 2005; revised 8 February 2005; accepted 9 February 2005
Abstract—A giant, 100-membered metallocycle 3 was prepared via coordination bond-based self-assembly from W-shaped ligand 9
and a palladium complex. Metallocycle 3 may create three topologically discrete subcavities, thus capable of binding up to three
molecules of a diamide guest by hydrogen-bonding interactions. Elemental analysis, 1H NMR, and the ESI-mass spectra, and vapor
pressure osmometry (VPO) data were all consistent with the structure of 3. N,N,N0,N0-tetramethylterephthalamide G was used as a
guest for the binding study, and ESI-mass spectrum clearly displayed a characteristic, intense peak at m/z 1542 (41%), attributed to
the fragment [3ÆG3-3CF3SO3]3+ of 1:3 (host/guest) complex. The 1H NMR titration experiments gave association constants of
2300 300 and 1200 200 Mꢀ1 in CDCl3 at 25 °C for two identical outer cavities, with weak positive cooperativity (Hill coefficient
h = 1.3).
Ó 2005 Elsevier Ltd. All rights reserved.
Reversible coordinative bonds between transition metals
and ligands have been widely used for self-assembly of
discrete supramolecular entities such as molecular
squares, polygons, and cages under thermodynamic con-
ditions over the past decade.1 Several transition metals
have been employed for this purpose, and Pd(II) and
Pt(II) have been proven to be highly versatile because
of reasonable strength of the coordination bonds and
of their suitability in both organic and aqueous solu-
tions. In early days, researches in this field were mainly
focused on the creation of two- or three-dimensional
structures, not available by conventional covalent syn-
thesis, but recently it has shifted to the construction of
more functional entities that can serve as artificial recep-
tors and that may have potentials as molecular materi-
als, machines, and devices.2
Metallocycle 2 can bind two molecules of a diamide
guest, one in each cavity, with a positive homotropic
cooperative manner, and it can therefore be considered
as a new kind of artificial allosteric model.5
Self-assembly of receptors that have well-defined, multi-
ple binding domains are extremely challenging and only
a few examples are known to date.5b,6 Herein, we de-
scribe the self-assembly and binding properties of a
O
O
N
R
O
O
O
R
R
NH
NH
HN
M
=
Os
O
N
N
R
N
N
M
M
Ph Ph
P
Pd
HN
P
We previously described self-assembly of metallocycles 1
and 2 that contain hydrogen-bonding sites inside the cav-
ities, thus functioning as artificial receptors for organic
molecules with complementary sizes, shapes, and func-
tional groups. For example, macrocycle 1 binds strongly
and selectively terephthalamide or adipamide derivatives
by hydrogen-bonding interactions in solution.3 More re-
cently, we reported the self-assembly of metallocycle 2,
which folded to generate two binding sites using S-
shaped bispyridyl ligands and a palladium compound.4
Ph Ph
N
O
O
1
O
O
O
O
N
N
NH
NH
HN
HN
NH
HN
HN
N
N
N
M
M
L
L
N
NH
N
N
O
O
O
O
*
Corresponding author. Tel.: +82 2 2123 2643; fax: +82 2 364 7050;
e-mail: ksjeong@yonsei.ac.kr
2
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.048

2434
H.-Y. Jang et al. / Tetrahedron Letters 46 (2005) 2433–2436
giant metallocycle 3, a 100-membered monocycle, that
can generate three topologically discrete subcavities.
Each of them possesses inside four amido NHs, and
therefore 3 can bind up to three molecules of a guest
by hydrogen-bonding interactions.
from 2:2 (ligand/metal) assembly. Elemental analysis
and 1H NMR integration indicate a 1:1 molar composi-
tion of the ligand and metal components. The pyridyl
C–H signals at both ends are downfield shifted
(d = 0.22 ppm) in the 1H NMR spectroscopy relative
to free ligand 9, as expected on the coordination of the
pyridyl nitrogen on the PdII center. The mass spectrum
of 3 in 50% (v/v) CH3CN/CHCl3 shows the fragments
of [3–3CF3SO3]3+ (m/z 1321, 4%) and [3–4CF3SO3]4+
(m/z 954, 15%), along with the fragments corresponding
to its complexes (Table 1) in the presence of N,N,N0,N0-
tetramethylterephthalamide (G) as a guest. In addition,
the VPO experiment9 with 3 in CHCl3 (benzil as a stan-
dard, 40 °C) gave a molecular weight of 4430 620 in
the range of concentrations between 11 and 29 gkgꢀ1
Syntheses of metallocycle 3 are summarized in Scheme
1. A W-shaped ligand 9 consists of three pyridine-2,6-
carboxamide units, which are connected with ethynyl
linkers by palladium-catalyzed reaction7 of compounds
7 and 8.4 The ethynyl group has been chosen as a linker
to minimize steric crowding around crossing points of
two ligand strands on the formation of metallocycle 3.
In addition, the methyl and isopropyl substituents on
the aryl rings greatly increase the solubility of 3, other-
wise insoluble, in less competitive solvents such as
CH2Cl2 and CHCl3. Ligand 9 smoothly self-assembled
into metallocycle 3 in the presence of a palladium com-
Table 1. ESI-mass data of 3 in the presence of excess G (ꢁ10 equiv) in
8
50% (v/v) CH3CN/CHCl3
plex Pd(dppp)OTf2 in 10% (v/v) CH3CN/CHCl3 at
Complex
Fragment
m/z (intensity (%))
room temperature. The reaction proceeded quantita-
tively within 30 min but the isolated yield was 91%. It
is worthwhile noting that presence of CH3CN (5–10%)
is critical for clean reaction, otherwise yielding a compli-
cated mixture.
3ÆG3 (1:3 complex)
3ÆG2 (1:2 complex)
[3ÆG3-3CF3SO3]3+
[3ÆG2-2CF3SO3]2+
[3ÆG2-3CF3SO3]3+
[3ÆG2-4CF3SO3]4+
[3ÆG1-3CF3SO3]3+
[3ÆG1-4CF3SO3]4+
[3-3CF3SO3]3+
1542 (41)
2277 (20)
1468 (49)
1064 (27)
1394 (18)
1008 (13)
1321 (4)
3ÆG1 (1:1 complex)
3 (unbound)
Elemental analyses, NMR and ESI-mass spectra, and
vapor pressure osmometry (VPO) experiments support
the structure of 3, a dinuclear metallocycle resulting
[3-4CF3SO3]4+
954 (15)
I
NH2
a
O
O
b
+
NH
NH
N
O
O
Cl
Cl
N
HN
O
I
N
HN
O
I
5
4
6
7
O
O
N
N
NH
HN
NH
7
N
O
N
N
HN
O
I
c
NH
HN
HN
NH
N
O
N
O
O
8
9
O
4+
O
O
O
O
O
O
N
N
N
NHa
HbN
HN
NHc
NH
NH
NH
HN
HN
Ph Ph
Ph Ph
P
Pd
P
N
N
N
N
P
d
Pd
P
Ph Ph
Ph Ph
HN
NH
HN
-
4 CF3SO3
N
N
N
O
O
O
O
O
O
3
Scheme 1. Synthesis of metallocycle 3. Reagents and conditions: (a) i-Pr2NEt, CH2Cl2, 0 °C to room temperature (97%); (b) Pd(PPh3)2Cl2, CuI,
triisopropylsilylethyne, THF, Et3N, 60–65 °C (75%), then Bu4NF, THF, 50–60 °C (97%); (c) Pd(PPh3)4, CuI, Et3N, THF, 60–65 °C (64%); (d)
Pd(dppp)OTf2, 10% CH3CN/CHCl3, room temperature (91%).

H.-Y. Jang et al. / Tetrahedron Letters 46 (2005) 2433–2436
2435
(sample/CHCl3), close to the calculated one (4415.4) for
3.
The energy-minimized structure10 of 3 presents three
topologically discrete subcavities11 resulting from zig-
zag folding. Each of them contains four conversing
NH groups capable of forming hydrogen bonds with
an appropriate dicarbonyl guest such as N,N,N0,N0-
tetramethylterephthalamide (G). The binding property
of 3 with G was first revealed with ESI-mass spectrom-
etry. The mass spectrum was taken with a mixture of 3
and excess G (ꢁ10 equiv) in 50% CH3CN/CHCl3 and
gave a characteristic, intense peak at m/z 1542 which is
attributed to the fragment [3ÆG3-3CF3SO3]3+ of the 1:3
complex. In addition, the fragments corresponding to
the 1:2 complex 3ÆG2 and the 1:1 complex 3ÆG1 are also
seen with reasonably strong intensities as summarized in
Table 1. This result implies that metallocycle 3 can bind
three molecules of the guest G in the gas phase. It should
be noted that the observed isotopic distributions for all
the fragments shown in Table 1, regardless of stoichio-
metries of the complexes, are in accordance with the theo-
retical ones calculated on the basis of metallocycle 3.
(see Supplementary Material).
Figure 1. 1H NMR titration curves plotting NH chemical shift changes
of 3 by increasing [G] and Jobplot (inset) showing the maximum
complexation at ꢁ0.34 mol fraction of 3.
hand, the chemical shift changes of the inner cavity
NHc are too small (Dd = 0.15 ppm) to determine reliably
the association constant (Ka < 20 Mꢀ1).
In conclusion, it has been demonstrated that the self-
assembly based on coordination bonds is highly efficient
for the preparation of a giant metallocycle with multiple
polar binding sites. The binding studies have proved
that the metallocycle binds up to three molecule of a di-
amide guest, one to each cavity, by hydrogen-bonding
interactions.
The binding properties in solution between 3 and G were
investigated in the 1H NMR spectroscopy. In metallocy-
cle 3, two cavities at both ends are identical but one in
the middle is different. As a result, 3 shows three differ-
ent 1H NMR signals for amide protons, NHa, NHb and
NHc. Addition of G to a CDCl3 solution of 3 induced all
three NH signals downfield shifted, but magnitudes of
the chemical shift changes were different. For example,
when G (5 mM) was added in a small portion to a solu-
tion of 3 (0.5 mM) at 25 °C, the NHa and NHb signals in
the outer cavities were gradually shifted from 9.00 and
8.73 ppm to 10.32 and 10.18 ppm, respectively (see
Fig. 1). Under the same conditions, the chemical shift
change in the inner cavity NHc was much smaller, from
8.88 to 9.03 ppm, implying that G binds much more
weakly to the inner cavity than to the outer cavities.
The reduced binding affinity of the inner cavity may
be attributed to two factors, steric effects and hydrogen
donor ability. That is, the inner cavity is surrounded by
four bulky isopropyl groups and thus sterically more
hindered, compared to the outer cavities bearing two
methyl and two isopropyl substituents. Furthermore,
the transition metal coordination on the terminal pyri-
dines increases the hydrogen donor ability of the amide
NHa protons in the outer cavities.
Acknowledgements
This work was financially supported by the Korea Insti-
tute of the Center for Bioactive Molecular Hybrids
(CBMH) and Science & Technology Evaluation and
Planning (M10213030001- 02B1503-00310).
Supplementary data
Synthesis, binding studies, VPO and ESI-mass experi-
ments of metallocycle 3. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.02.048.
References and notes
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The association constants for two outer cavities were
determined by nonlinear curve fitting methods using
the HOSTEST program developed by Wilcox,12 and
were found to be 2300 300 and 1200 200 Mꢀ1 for
K1 (=[3ÆG1]/[3][G]) and K2 (=[3ÆG2]/[3ÆG1][G]), respec-
tively. Considering the relationship of K2 = 1/4K1 for
non-cooperative binding, these values reflect slightly po-
sitive cooperativity, which was confirmed by the Hill
coefficient h = 1.3.13 In addition, Jobꢀs plots13 also sup-
port a 1:2 (3/G) binding mode, showing the highest con-
centration of the complex at approximately 0.33 mol
fraction of 3 in CDCl3 (see Fig. 1, inset). On the other
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